WO2000010549A1 - Regulation of substrate activity - Google Patents
Regulation of substrate activity Download PDFInfo
- Publication number
- WO2000010549A1 WO2000010549A1 PCT/US1999/018315 US9918315W WO0010549A1 WO 2000010549 A1 WO2000010549 A1 WO 2000010549A1 US 9918315 W US9918315 W US 9918315W WO 0010549 A1 WO0010549 A1 WO 0010549A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- formula
- compound
- alkyl
- dpp
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- This invention relates to inhibitors for dipeptidyl peptidase IV which are used to regulate substrate activity.
- substrate denotes chemokines, cytokines and biological peptides which are substrates for DPP-IV.
- This invention also relates to the use of DPP-IV inhibitors in the treatment of medical disorders which may result from the inactivation of substrates implicated in the medical disorder.
- dipeptidyl peptidase IV is alternatively described as "DPP-IV,” “DP-IV” and “CD26.”
- CD26 is an ectoenzyme with activity identical to that of DPP-IV.
- DPP-IV is a serine type exopeptidase with high substrate specificity cleaves N- terminal dipeptides from proteins if the penultimate amino acid is proline, or in some cases alanine (Fleischer, B. Immunol. Today 15:180 (1994)).
- CD26 have previously been developed and characterized (G.R. Flentke et al., Inhibition of dipeptidyl aminopeptidase IV (DP-IV) by Xaa-boroPro dipeptides and use of these inhibitors to examine the role of DP-IV in T-cell function, PNAS (USA) 88, 1556-1559 (1991); W.G. Gutheil and W.W. Bachovchin, Separation of L-Pro-DL-boroPro into Its Component Diastereomers and Kinetic Analysis of Their Inhibition of Dipeptidyl Peptidase IV: A New Method for the Analysis of Slow, Tight-Binding Inhibition, Biochemistry 32, 8723-8731 (1993)). These molecules have been shown to be potent and specific synthetic inhibitors for CD26- associated DP-IV proteinase activity.
- Xaa-boroPro Representative monomeric structures of these transition-state-analog-based inhibitors, Xaa-boroPro, wherein Xaa is an amino acid residue, include Pro-boroPro, Ala-boroPro, Val- boroPro, and Lys-boroPro.
- BoroPro refers to the analog of proline in which the carboxylate group (COOH) is replaced with a boronyl group [B(OH) 2 ].
- Pro-boroPro the most thoroughly characterized of these inhibitors, has a Ki of 16 picomolar (pM) (W.G. Gutheil and W.W. Bachovchin, supra).
- Val-boroPro has an even higher affinity, with a Ki of 1.6 pM (W.G. Gutheil and W.W. Bachovchin, supra; R.J. Snow et al., Studies on Proline Boronic Acid
- Dipeptide Inhibitors of Dipeptidyl Peptidase IV Identification of a Cyclic Species Containing a B-N Bond, J. Am. Chem. Soc. 116, 10860-10869 (1994)). Thus, these Xaa-boroPro inhibitors are about 10 +6 fold more potent than the next best known inhibitors.
- Chemokines or chemoattractant cytokines, are a family of small proteins with a conserved cysteine motifs. These small proteins have been implicated in a wide range of disease states, such as acute and chronic inflammatory processes, angiogenesis, leukocyte migration, regulation of cell proliferation and maturation, hematopoiesis, viral replication, and other immunoregulatory functions. Chemokines are expressed by a number of different cells and have distinct but overlapping cellular targets.
- CXC CXC chemokines
- CX3C-chemokines CX3C-chemokines
- MCP-1 and RANTES are potent direct mediators of the release of histamine by human basophils. Both groups of chemokines are involved in lymphocyte migration to inflammatory sites.
- chemokine receptors are transmembrane spanning molecules which belong to the family of G-protein-coupled receptors. Many of these receptors couple to guanine nucleotide binding proteins to transmit cellular signals. Chemokines and receptor expression is upregulated during inflammatory responses and cellular activation. Chemokines, through binding to their respective receptors, have been shown to be involved in a number of physiologic conditions. For instance, chemokines of the CXC group, like Interleukin-8, can stimulate angiogenesis, while Platelet Factor-4, growth-related oncogene- ⁇ (GRO- ⁇ ) and interferon- ⁇ induced Protein- 10 (IP- 10) inhibit endothelial cell proliferation and angiogenesis.
- CXC group like Interleukin-8
- GRO- ⁇ growth-related oncogene- ⁇
- IP- 10 interferon- ⁇ induced Protein- 10
- Interleukin-8 stimulates endothelial cell proliferation and chemotaxis in vitro, and appears to be a primary inducer of macrophage induced angiogenesis. It was shown that the activities of these chemokines are dependent on the NH 2 -terminal amino acid sequence (Streiter et al., J Biol. Chem., 270; pages 27348-27357). SDF-1, another CXC chemokine, is active in the recruitment and mobilization of hematopoietic cells from the bone marrow, as well as the attraction of monocytes and lymphocytes. In addition, it interferes with cellular infection of HIV-1 by blocking the interaction of HIV- 1 with CXCR-4. As with other chemokines in this group, the amino terminal sequence regulates its activity (Shioda, T., et al., PNAS, 95; pages 6331-6336).
- Chemokine receptors have been shown to serve not only as receptors to chemokines, but most recently have been identified as receptors for a variety of microbes and the HIV-1 virus.
- the Duffy blood group Ag a chemokine receptor on erythrocytes, is the receptor for the malaria parasite Plasmodium vivax, and the platelet activating receptor is a receptor for Streptococcus pneumonia.
- chemokines such as RANTES, MIP-1 and SDF-1, or cytokines like IL-2, or peptides like GLP-1, GLP-2, and Substance P, are substrates for DPP-IV.
- DPP-IV cleaves peptides at the NH 2 terminus if the penultimate amino acid is proline.
- cytokines and chemokines have the conserved sequence NH 2 X-Pro-X, and have been shown to be substrates for DPP-IV.
- DPP-IV is expressed on the surface of T cells and macrophages. The relationship of CD26 protease activity to its immune function is not clear, however there are indications that cleavage by CD26 of the NH 2 -dipeptide of several cytokines changes their receptor specificity and/or their functional activities.
- Cytokines that are known to be potential substrates for DPP-IV include G-CSF, erythropoietin, IL-l ⁇ , IL-2, IL-3, IL-6, IL-11, TNF- ⁇ and GM-CSF.
- a number of biologically active peptides have, on their amino termini, the amino acid sequence Xaa-Pro-Xaa, which serves as the substrate for DPP-IV.
- these are the Glucagon Like Peptides, GLP-1 and GLP-2.
- GLP- 1 is involved in insulin release and glucose uptake, and cleavage by DPP-IV causes inactivation of its activity. Inhibition of DPP-IV will result in the prolonged activation state of this peptide, and represents a therapeutic indication of DPP-IV inhibitors.
- GLP-2 peptide is involved in intestinal growth and nutrient uptake, and increased activity of GLP-2 will result in an increased nutrient uptake for individuals with intestinal diseases.
- CD26 is known to be highly expressed on hepatosplenic T cell lymphoma, and DPP-IV activity, or the ability of CD26 to bind to collagen fibronectin on the extracellular matrix, may be part of the pathogenic mechanism utilized in by neoplastic cells (Ruiz et al., Cytometry 1998, 34: pages 30-35). DPP-IV and DPP-II levels are known to be significantly increased in the gingival crevicular fluid of patients with periodontitis. Increased levels of these two proteases seem to be associated with increased attachment loss. It is believed that collagen-CD26 interactions are a part of the pathological observations.
- PCT published application WO 95/11689 discloses the use of inhibitors of DPP-IV to block CD26, thereby blocking entry of HIV into CD26-bearing cells.
- These inhibitors are tetrapeptides having the general formula X-Pro-Y-boroPro where X and Y are chosen from any amino acid.
- the dipeptides are also disclosed, the reference states that dipeptides are unstable, and tetrapeptides are preferred.
- the inhibitors are used to treat pre-symptomatic HIV-infected patients not by neutralizing the virus, but by blocking viral entry into the cells. The reference does not disclose the effect of DPP-IV inhibition on chemokine activity.
- a method for the treatment of a medical disorder in a patient which is mediated by substrate activity.
- a pharmaceutical composition is administered to the patient in an amount which is effective to inhibit DPP-IV activity.
- This pharmaceutical composition contains, as an active ingredient, a compound represented by the general formula PR, where P is a targeting moiety that binds to DPP-IV, and R is a reactive group that reacts with a functional group in DPP-IV, preferably a reactive center of DPP-IV.
- the active ingredient is a compound comprising an amino group covalently bonded to an alpha-amino boronic acid analog of proline (the term "boroPro" is used herein to designate such an analog having the carboxyl group of proline replaced with a B(OH) 2 group, where (OH) 2 represents two hydroxyl groups and B represents boron).
- the active ingredient can therefor be designated as Xaa-boroPro, where Xaa is an amino acid residue.
- the active ingredient is Val-boroPro wherein the carboxy terminal boroProline is coupled via a peptide linkage in accordance with standard peptide chemistry to a valine amino acid residue.
- This active ingredient acts to suppress DPP-IV activity for those substrates which are DPP-IV substrates, resulting in an increase in bioavailability of active chemokine in vivo.
- the net effect is a positive therapeutic benefit to the patient, particularly with respect to certain disease states, such as inflammation, angiogenesis, arteriolosclerosis, intestinal diseases, diabetes, anorexia, and anti-tumor activity, which could not have been predicted on the basis of current knowledge of DPP-IV activity or inhibition.
- Substrates which are applicable to the method of this invention include those which share a conserved NH 2 -X-Pro sequence (where X is any amino acid or a short peptide). These substrates for DPP-IV, and their activity is altered upon cleavage of the N-terminal sequence. The altered substrates can theoretically possess either enhanced or attenuated activity, but they will most typically be inactivated to some extent.
- Specific examples of chemokines which are inactivated by DPP-IV include, but are not limited to, SDF-1, RANTES, MIP-3. The inhibition of DPP-IV activity prevents the digestion of chemokines, cytokines and growth factors.
- the substrates of this invention are implicated in a variety of disease states, including inflammation, arteriolosclerosis, angiogenesis, and anti-tumor activity. Inhibition of DPP-IV by the active compounds of this invention is believed to result in the bioavailability of the substrates for enhancing responses to medical trauma.
- the pharmaceutical composition will typically include the active component (preferably Xaa-boroPro, and most preferably Val-boroPro), and a pharmaceutically acceptable carrier.
- the pharmaceutical composition can also include various adjuvants, enhancers, cytokines, etc., as are known to those skilled in the art. Patient dosages will generally be within the range of 0.001 mg/kg to 100 mg/kg.
- Figure 1 shows the bioavailability of PT-100 (Val-boroPro), and the HC1 and methane sulfonate salts of PT- 100.
- the invention involves the use of certain compounds to inhibit DPP-IV activity when appropriately administered to a subject.
- subject is intended to mean a human, non-human primates, dogs, cats, sheep, goats, horses, cows, pigs and rodents.
- the subject is a human patient undergoing medical treatment.
- DPP-IV acts on the substrates in vivo to cleave the two N-terminal sequence where the penultimate amino acid is proline.
- other peptidases such as peptides A or N could cleave the terminal sequence to expose the Xaa-Pro-Xaa moiety. This cleavage may result in altering the receptor specificity or functionality of the substrate, and typically will result in changes of the activity of the substrate. This may directly effect the patient's response to a particular medical disorder or trauma.
- chemokines such as SDF-1, MIP-1 and RANTES
- DPP-IV Cleavage of these chemokines by DPP-IV alters their activity and affects the migration of the lymphocytes to the site of an inflammation, hematopoiesis or immune function.
- the DPP-IV inhibitor acts to block DPP-IV from cleaving the chemokine, either through competitive interaction with DPP-IV or attachment to the active site.
- Compounds useful in the invention include, but are not limited to, compounds that inhibit DPP-IV and are embraced by the formula PR, wherein P represents a targeting moiety that binds to DPP-IV and R represents a reactive group that reacts with a functional group in DPP-IV, preferably a reactive center of DPP-IV.
- P can be any molecule that binds DPP-IV, including DPP-IV binding molecules embraced by the formula: D ⁇ A, -A 2 -A 3 -A 4 , wherein D is independently selected from the group consisting of NH and NH 2 , wherein N represents any isotope of nitrogen, wherein H represents any isotope of hydrogen; " ⁇ ", independently, is selected from the group consisting of a single bond and a double bond; A, is selected from the group consisting of a C, a CX and an N, wherein C represents any isotope of carbon, X represents any atom that forms a single bond with carbon; each A 2 , A 3 , and A 4 , independently, is selected from the group consisting of a CX moiety, a CXZ moiety, a CZ moiety, a NX moiety, and an O, wherein X and Z, independently are selected from the group consisting of any atom that forms a single bond and any atom that forms a double bond
- Group I has the structure:
- H represents a hydrogen
- C represents a carbon
- O represents an oxygen
- N represents a nitrogen
- each R independently, is chosen from the group consisting of the R groups of an amino acid, including proline
- X represents any atom that forms a single bond with carbon, including hydrogen and halogens
- Y is
- each R legion R 2 , R 3 , R 4 , R 5 , Rg, R 7 , and R 8 separately is a group which does not significantly interfere with site specific recognition of the inhibitory compound by DPP-IV, and allows a complex to be formed with DPP-IV.
- Rj-Rg are H each H represents a hydrogen atom; and q and p are integers which are independently varied between 0 and 4 inclusive.
- Group I has the structure:
- each G 2 and G 3 independently is H or C r C 3 (one to three carbon atoms) alkyl; G, is NH 3 (H 3 represents three hydrogens); or G, is
- G (H 2 represents two hydrogens), or G, is NG 4 , where G 4 is C-G 5 I 5 G-6
- G 5 and G 6 can be NH, H, or C,-C 3 alkyl or alkenyl with one or more carbons substituted with a nitrogen. G, bears a charge, and G, and G 2 do not form a covalently bonded ring structure at pH 7.0.
- Group I may also have the structure:
- Group I may also include a five membered unsaturated ring having two nitrogen atoms, e.g., an imidazole ring.
- Group II has the structure:
- T is a group of the formula:
- each D, and D 2 independently, is a hydroxyl group or a group which is capable of being hydrolyzed to a hydroxyl group in aqueous solution at physiological pH; or T is a group of the formula: -C-CF-G II I O F
- G is either H, F, or an alkyl group containing 1 to 20 carbon atoms and, optionally, heteroatoms which can be N, S or O; or T is a phosphonate group of the formula:
- each J independently, is any number of N, H, C, O or S atoms, in any combination, or O-alkyl, N-alkyl, or alkyl, each O-alkyl, N-alkyl or alkyl containing 1-20 carbon atoms and, optionally, heteroatoms which can be N, S, or O; or T is
- R is an alkyl, or aryl group and may be substituted or unsubstituted, an alphaketo ester;
- T is generally able to form a complex with the catalytic side of a DPP-IV.
- Y is: I ⁇ ⁇ R4 Rs R 7 j C— R, , 3— C— C-Rg , or R3— C— C— C— Rg
- each R,, R 2 , R 3 , R 4 , R 5 , Rg, R 7 , and R 8 separately is a group which does not significantly interfere with site specific recognition of the inhibitory compound by DPP-IV, and allows a complex to be formed with DPP-IV.
- R,-R g are H.
- X is any number of C, H, O, S, or N atoms, in any combination, including any amino acid or organic molecule, and m can vary from 0 to 20.
- T is a boronate group, a phosphonate group, a cyano group, or a trifluoroalkyl ketone group; each R,-R g , is H; each R, and R 2 is H, and each Y is CH 2 - CH 2 ; each R is independently chosen from the R group of proline and alanine; the inhibitory compound has a binding or dissociation constant to DPP-IV of at least 10 "9 M, 10 ⁇ 8 M or even 10 "7 M; and each Dl and D2 is, independently, F or Dl and D2 together are a ring containing 1 to 20 carbon atoms, and optionally heteroatoms which can be N, S, or O.
- each D, and D 2 independently, is a hydroxyl group or a group which is capable of being hydrolyzed to a hydroxyl group in aqueous solution at physiological pH; and wherein X is a targeting moiety that mimics the site of a substrate recognized and cleaved by DPP-IV, and preferably is an amino acid, an imino acid, or a peptide which mimics the site of a substrate recognized by a post prolyl cleaving enzyme; C is bonded to B in the L- configuration; and the bonds between B and C, and between Y and N are peptide bonds.
- C is bonded to B in the L-configuration
- the active Xaa-boroPro compound of this invention can have an open chain (linear) form or a cyclic form.
- the linear form can be converted to the cyclic form by a trans to cis isomerization of the proline, and the formation of a new N-B bond.
- cyclic form refers to the cyclized structure of the compounds described in the foregoing formula that are the boron analogs of diketopiperazine.
- the active compound is an Xaa-boroPro compound, and still more preferably is a Val-boroPro compound.
- a "Val- boroPro compound” refers to a compound as defined in the formula above in which the carboxy terminal boroPro is covalently coupled via a peptide linkage in accordance with standard peptide chemistry to a valine amino acid residue.
- the compound of the invention is Val-boroPro (also referred to by the manufacturer's designation "PT- 100").
- the preferred active compounds have targeting moieties that are peptides which mimic the substrate binding site of DPP-IV.
- Peptide analogs and nonpeptides or peptidomimetics also can be used as targeting moieties.
- Such molecules can be rationally designed based upon the known sequence of substrates of DPP-IV or can be identified using combinatorial chemistry and screening assays such as are described below.
- phage display libraries and chemical combinatorial libraries permits the selection of synthetic compounds which mimic the substrate binding site of a protease such as DPP-IV.
- Such libraries can be screened to identify non-naturally occurring putative targeting moieties by assaying protease cleavage activity in the presence and absence of the putative phage display library molecule or combinatorial library molecule and determining whether the molecule inhibits cleavage by the protease of its natural substrate or of a substrate analog (e.g., a chromophoric substrate analog which is easily detectable in a spectrophotometric assay).
- a substrate analog e.g., a chromophoric substrate analog which is easily detectable in a spectrophotometric assay.
- Those phage library and/or combinatorial library molecules which exhibit inhibition of the protease then can be covalently coupled to the reactive groups R disclosed herein and again tested to determine whether these novel molecules selectively bind to the protease (e.g., by repeating the above-noted screening assay). In this manner, a simple, high-through-put screening assay is provided for identifying non-naturally occurring targeting moieties of the invention.
- the substrates of this invention are those substrates which share a conserved NH 2 -X- Pro sequence (where X is any amino acid or a short peptide) at the NH 2 terminus of the molecule.
- Substrates having this structural configuration act as substrates for DPP-IV.
- the inhibitory effect of the present compounds on DPP-IV serves to increase the bioavailability of the substrate in the subject, which in turn results in a positive biological result. For instance, increased bioavailability of selected substrates can produce an increase in immune and anti- inflammatory function in the subject.
- Suitable substrates are known in the art, but until now, no one has correlated the use of DPP-IV inhibitors with a positive medical effect on those conditions which are mediated by the presence and activity of the substrates.
- SDF-1 stromal cell-derived factor 1
- SDF-1 acts on lymphocytes and monocytes but not neutrophils in vitro, and is an effective and potent mononuclear cell attractant in vivo.
- SDF-1 is expressed in a broad range of tissues, it may assist in the treatment of arteriolosclerosis, and it also may have anti-HIV activity.
- MIP-1 macrophage inflammatory protein- 1
- RANTES regulated on activation, normal T-cell expressed and secreted modulates integrin adhesion and has also been implicated in inflammatory diseases.
- GLP-1 insulin-like peptide- 1
- DPP-IV inhibition using the active compounds of this invention, would potentiate its insulinotropic effects, and may provide assist in the treatment of diabetes.
- GLP-2 (glucagon-like peptide-2) is known to stimulate small intestinal growth through the induction of intestinal epithelial proliferation. GPL-2 is also inactivated by DPP-IV in vivo. DPP-IV inhibition may result in increased capacity for nutritional digestion and absorption in vivo, and provide a treatment for AIDS, anemia and anorexia. GLP-2 may be therapeutically useful to enhance mucosal regeneration in patients with intestinal diseases. Inhibition of DPP-IV promotes the absorption of enterostatin and desanginine-enterostatin across rat jejunum.
- G-CSF granulocyte-colony stimulating factor
- EPO erythropoietic-6
- red blood cell growth factor is a growth factor for hematopoietic cells such as neutrophils.
- IL-6 (Interleukin-6) is a hematopoietic and lymphocyte growth factor.
- IL-11 (Interleukin-11) is a lymphokine.
- IL-8 (Interleukin-8) is a hematopoietic growth factor, angiogenesis cytokine.
- Substance P is a neuropeptide and a hematopoietic growth factor.
- Other suitable chemokines include Substance P, which has vasoactive properties, monomeric fibrin, which effects blood clotting, fibronectin, which promotes binding of hepatocytes and could enhance liver regeneration, MIP-3, a chemoattractant for B-cells, and collagen types I, II, III, and IV, which regulate in part the migration of a number of effector cells, including T cells, across the endothelial barrier.
- Other medical disorders which may be treated according to the method of this invention include allergies, angiogenesis, cardiogenesis, anti-tumor responses, hepatic disease, and organ vascularization.
- the compounds of the invention or compositions thereof can be administered alone or in combination with one another, or in combination with other therapeutic agents.
- treatment with one or more of the compounds of the invention can be combined with more traditional therapies for treating medical disorders, or combined with other cytokines to enhance treatment success.
- the pharmaceutical preparations of the invention are applied in pharmaceutically-acceptable amounts and in pharmaceutically-acceptably compositions.
- Such preparations may routinely contain salt, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents.
- the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the invention.
- Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like.
- pharmaceutically-acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.
- the pharmaceutical compositions also may contain, optionally, suitable preservatives, such as: benzalkonium chloride; chlorobutanol; parabens and thimerosal.
- suitable preservatives such as: benzalkonium chloride; chlorobutanol; parabens and thimerosal.
- Carrier formulation suitable for oral, subcutaneous, intravenous, intramuscular, etc., administrations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
- compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, lozenges, each containing a predetermined amount of the compound of the invention.
- compositions include suspensions in aqueous liquids or non-aqueous liquids such as a syrup, elixir or an emulsion.
- the oral preparation may include an enteric coating.
- parenteral includes subcutaneous, intravenous, intramuscular, or infusion.
- Compositions suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the compound, which is preferably isotonic with the blood of the recipient. This aqueous preparation may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation also may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 -butane diol.
- a non-toxic parenterally-acceptable diluent or solvent for example, as a solution in 1,3 -butane diol.
- acceptable vehicles and solvents that may be employed are water. Ringer's solution, and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or di-glycerides.
- fatty acids such as oleic acid may be used in the preparation of injectables.
- Intravenous or intramuscular routes are not particularly suitable for long-term therapy and prophylaxis. They could, however, be preferred in emergency situations. Oral administration will be preferred for prophylactic and other treatment because of the convenience to the patient as well as
- compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy.
- the methods include the step of bringing the compounds of the invention into association with a carrier which constitutes one or more accessory ingredients.
- the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
- Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the compounds described above, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art.
- polymer base systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides.
- Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Patent 5,075,109.
- Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono- di- and tri-glycerides; hydrogel release systems; sylastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like.
- Specific examples include, but are not limited to: (a) erosional systems in which the compound is contained in a form within a matrix such as those described in U.S. Patent Nos. 4,452,775, 4,667,014, 4,748,034 and 5,239,660 and (b) diffusional systems in which an active component permeates at a controlled rate from a polymer such as described in U.S. Patent Nos. 3,832,253, and 3,854,480.
- pump- based hardware delivery systems can be used, some of which are adapted for implantation.
- Long-term sustained release implant may be particularly suitable for treatment of chronic conditions.
- Long-term release means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 10 days, and preferably 60 days.
- Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.
- the compounds described herein are administered in effective amounts.
- An effective . amount is a dosage of the compound sufficient to provide a medically desirable result. The effective amount will vary with the particular condition being treated, the age and physical condition of the subject being treated, the severity of the condition, the duration of the treatment, the nature of the concurrent therapy (if any), the specific route of administration, and like factors within the knowledge and expertise of the health practitioner.
- An effective amount for stimulating a desired immune response also can be measured, for example, by determining a change in the immune function in a subject (e.g., increased B cell response, increased cytotoxic T cell response, or an ability to slow, halt, or prevent an infection).
- An effective amount for treating an autoimmune disorder or allergic disorder would be that amount sufficient to lessen or inhibit altogether the immune or allergic response associated with the disorder so as to slow or halt the development of or the progression of the disorder.
- "inhibit" embraces all of the foregoing.
- an effective amount for treating an immune system disorder is that amount which can slow or halt altogether the symptoms associated with the immune system disorder so as to prevent the disorder, slow its progression, or halt the progression of the immune system disorder. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.
- doses of active compounds will be from about 0.001 mg/kg per day to 1000 mg/kg per day. It is expected that doses range of 0.01 to 100 mg/kg per day will be suitable, preferably orally and in one or several administrations per day. Lower doses will result from other forms of administration, such as intravenous administration. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
- H-boroPro As taught in WO 98/00439.
- Use of H-boroPro is for illustrative purposes only, and is not intended to limit the scope of this invention.
- H-boroPro was prepared by the synthetic route previously developed and described (G.R. Flentke, et al., "Inhibition of dipeptidyl aminopeptidase IV (DP-IV) by Xaa-boroPro dipeptides and use of these inhibitors to examine the role of DP-IV in T-cell function," PNAS (U.S.A.) 88, 1556-1559 (1991); also described in United States Patent No. 5,462,928).
- H-boroPro may be produced by a new procedure (Kelly, T.A., et al., "The efficient synthesis and simple resolution of a proline boronate ester suitable for enzyme inhibition studies," Tetrahedron 49, 1009-1016 (1993)). Both of these synthetic routes reportedly yield racemic H-boroPro pinanediol.
- stereochemically pure L, L and L, D diastereomers of Z- Lys-boroPro were prepared by first resolving racemic H-boroPro through crystallization with optically active blocking protecting groups ((IS, 2S, 3R, 5S)-+-pinanediol isomer) followed by coupling the isotopically pure L-boroPro and D-boroPro to the stereochemically pure L isomer of lysine (See United States Patent No. 5,462,928).
- optically active blocking protecting groups (IS, 2S, 3R, 5S)-+-pinanediol isomer
- the L,L and L,D diastereomers of Lys-boroPro were prepared in high optical purity by coupling racemic H- boroPro by L-Lys and separating the resulting diastereomeric Z-Lys-boroPro-diester into its component L,D and L,L diastereomers using reverse phase HPLC as previously described for diastereomeric Pro-boroPro (W.G. Gutheil and W.W. Bachovchin, "Separation of L-Pro-DL- boroPro into Its Component Diastereomers and Kinetic Analysis of Their Inhibition of Dipeptidyl Peptidase IV. A New Method for the Analysis of Slow, Tight-Binding Inhibition," Biochemistry 32, 8723-8731 (1993)).
- the inhibitors exist as a slowly equilibrating mixture of two conformations: an open chain structure (linear boroProline compound) which is inhibitory (active species), and a cyclic structure (cyclic boroProline compound) which is non-inhibitory (inactive species).
- the open, active, inhibitory chain species is favored at low pH while the cyclized structure is favored at neutral pH.
- the reaction is fully reversible: the open chain becomes predominant at low pH.
- the open chain to cyclic species reaction involves a trans to cis isomerization of the proline and the formation of a new N-B bond.
- the cyclized structure is the boron analog of a diketopiperazine, a product often seen in peptide chemistry. Cyclization liberates one equivalent of H+ thereby explaining the requirement for base in the cyclization reaction and acid in the opening reaction.
- the cyclic structure is quite stable in aqueous solutions of high pH.
- the inventors believe that the cyclic compounds of the invention have the ability to specifically bind to CD26. Accordingly, the inventors predict that the biological function of the compounds of the invention could be significantly increased (approximately 100-1000 times) by orally administering the cyclic compounds of the invention and permitting the conformational changes, e.g., linearization, to occur in vivo (e.g., under the acidic conditions of the stomach). Thus, if linearization is necessary, it can be accomplished in vivo and therefore, therapeutic concentrations in the systemic circulation can be generated in situ and, accordingly, it is believed that the bioactivity of the compounds of the invention can be increased by approximately 100 - 1000 fold. In addition, it is believed that the cyclic boroProline compounds of the invention, in lyophilized or solid form, have improved shelf life properties, thereby contributing to the further utility of the compounds of the invention.
- Each of the compounds prepared as described above can be purified to homogeneity using HPLC and its identity can be confirmed by NMR spectroscopy, amino acid composition, or mass spectroscopy as deemed necessary.
- the cyclic compounds of the invention can be converted to linear form by adjusting the pH to an acidic pH (e.g., pH range: 1-3) and the potency of inhibition of CD26 proteinase activity by the linear boroProline compounds can be determined using conventional enzyme analysis (example provided below).
- an acidic pH e.g., pH range: 1-3
- the potency of inhibition of CD26 proteinase activity by the linear boroProline compounds can be determined using conventional enzyme analysis (example provided below).
- the immunomodulatory effects of the compounds of the invention are evaluated by in vivo experiments using animal models and by in vitro experiments using cell culture methods that are believed by those of ordinary skill in the art to be predictive of an in vivo activity.
- the compounds of the invention have at least the following properties: (I) binding site is the DPP-IV active site; and (ii) exhibit cross-species specificity.
- the assays which are used to assess functional activity include: DPP-IV activity, oral and subcutaneous bioavailability assays, and are described below.
- Assays to measure DPP-IV activity can be performed on the compounds of the invention.
- Methods for quantitatively measuring the interaction of small peptidomimetic inhibitors with DPP- IV, as well as for the interaction of CD26 with larger ligands, e.g., the HIV Tat protein have been developed (W.G. Gutheil and W.W. Bachovchin. Separation of L-Pro-DL-boroPro into Its Component Diastereomers and Kinetic Analysis of Their Inhibition of Dipeptidyl Peptidase IV. A New Method for the Analysis of Slow, Tight-Binding Inhibition, Biochemistry 32, 8723-8731 (1993); Gutheil, W.G., and W., B.W.
- mice received PT-100 at indicated doses by gavage. Blood samples are taken two hours post administration and serum DPP-IV activity is determined. DPP-IV activity is measured in a fluorometric assay using the synthetic substrate 7-amino-4- trifluoromethyl coumarin (AFC)-AlaPro (15). Total inhibition of serum DPP-IV activity is achieved at doses of 2 ⁇ g or 5 ⁇ g PT-100. Doses below 2 ⁇ g result in a dose dependent decrease of DPP-IV inhibition.
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99941081A EP1104293A1 (en) | 1998-08-21 | 1999-08-13 | Regulation of substrate activity |
IL14147199A IL141471A0 (en) | 1998-08-21 | 1999-08-13 | Regulation of substrate activity |
AU54801/99A AU5480199A (en) | 1998-08-21 | 1999-08-13 | Regulation of substrate activity |
JP2000565871A JP2002523365A (en) | 1998-08-21 | 1999-08-13 | Regulation of substrate activity |
KR1020017002162A KR20010079669A (en) | 1998-08-21 | 1999-08-13 | Regulation of Substrate Activity |
CA002339537A CA2339537A1 (en) | 1998-08-21 | 1999-08-13 | Regulation of substrate activity |
BR9913153-6A BR9913153A (en) | 1998-08-21 | 1999-08-13 | Normalization of substrate activity |
US09/744,658 US6979697B1 (en) | 1998-08-21 | 1999-08-13 | Regulation of substrate activity |
NO20010844A NO20010844L (en) | 1998-08-21 | 2001-02-19 | Regulation of substrate activity |
US11/190,487 US7265118B2 (en) | 1998-08-21 | 2005-07-27 | Regulation of substrate activity |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US9737698P | 1998-08-21 | 1998-08-21 | |
US60/097,376 | 1998-08-21 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09744658 A-371-Of-International | 1999-08-13 | ||
US11/190,487 Continuation US7265118B2 (en) | 1998-08-21 | 2005-07-27 | Regulation of substrate activity |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000010549A1 true WO2000010549A1 (en) | 2000-03-02 |
Family
ID=22263045
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/018315 WO2000010549A1 (en) | 1998-08-21 | 1999-08-13 | Regulation of substrate activity |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1104293A1 (en) |
JP (1) | JP2002523365A (en) |
KR (1) | KR20010079669A (en) |
AU (1) | AU5480199A (en) |
BR (1) | BR9913153A (en) |
CA (1) | CA2339537A1 (en) |
IL (1) | IL141471A0 (en) |
NO (1) | NO20010844L (en) |
WO (1) | WO2000010549A1 (en) |
Cited By (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000071135A1 (en) * | 1999-05-25 | 2000-11-30 | Point Therapeutics, Inc. | Anti-tumor comprising boroproline compounds |
US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
WO2002053170A2 (en) | 2001-01-02 | 2002-07-11 | Institut Für Medizintechnologie Magdeburg Gmbh (Imtm) | Combined use of enzyme inhibitors and pharmaceutical preparations thereof for the treatment and prophylaxis of arteriosclerosis, for the treatment and prevention of allergic reactions of type i according to the gell and coombs classification, and for the treatment and prevention of dermatological diseases associated with fo |
WO2003002595A2 (en) * | 2001-06-27 | 2003-01-09 | Probiodrug Ag | Dipeptidyl peptidase iv inhibitors and their uses as anti-cancer agents |
WO2003045228A2 (en) * | 2001-11-26 | 2003-06-05 | Trustees Of Tufts College | Methods for treating autoimmune disorders, and reagents related thereto |
WO2003099279A1 (en) * | 2002-05-29 | 2003-12-04 | Novartis Ag | Combination of a dpp iv inhibitor and a cardiovascular compound |
US6770620B2 (en) | 2000-09-18 | 2004-08-03 | Sanos Bioscience A/S | Use of GLP for the treatment, prevention, diagnosis, and prognosis of bone-related and nutrition-related disorders |
US6844316B2 (en) | 2001-09-06 | 2005-01-18 | Probiodrug Ag | Inhibitors of dipeptidyl peptidase I |
US6890905B2 (en) | 2001-04-02 | 2005-05-10 | Prosidion Limited | Methods for improving islet signaling in diabetes mellitus and for its prevention |
US6890904B1 (en) | 1999-05-25 | 2005-05-10 | Point Therapeutics, Inc. | Anti-tumor agents |
WO2005049022A2 (en) * | 2003-11-17 | 2005-06-02 | Novartis Ag | Use of dipeptidyl peptidase iv inhibitors |
US6946480B2 (en) | 2002-02-28 | 2005-09-20 | Hans-Ulrich Demuth | Glutaminyl based DPIV inhibitors |
US6949515B2 (en) | 1999-08-24 | 2005-09-27 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV for topical use |
US6979697B1 (en) | 1998-08-21 | 2005-12-27 | Point Therapeutics, Inc. | Regulation of substrate activity |
US7067489B2 (en) | 1998-05-04 | 2006-06-27 | Point Therapeutics, Inc. | Hematopoietic stimulation |
US7078381B2 (en) | 1998-02-02 | 2006-07-18 | Trustees Of Tufts College | Method of regulating glucose metabolism, and reagents related thereto |
US7109347B2 (en) | 2001-06-27 | 2006-09-19 | Probiodrug Ag | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
CN1292747C (en) * | 2003-09-16 | 2007-01-03 | 广东省心血管病研究所 | Compound formulation for treating hypertension |
US7166579B2 (en) | 1998-06-24 | 2007-01-23 | Prosidion Limited | Prodrugs of DP IV-inhibitors |
EP1806138A1 (en) * | 1999-05-25 | 2007-07-11 | Point Therapeutics, Inc. | Anti-tumor agents comprising boroproline compounds |
WO2007085895A2 (en) * | 2005-09-02 | 2007-08-02 | Ferring B.V. | Fap inhibitors |
WO2007120702A2 (en) | 2006-04-11 | 2007-10-25 | Arena Pharmaceuticals, Inc. | Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto |
US7368421B2 (en) | 2001-06-27 | 2008-05-06 | Probiodrug Ag | Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis |
US7371871B2 (en) | 2003-05-05 | 2008-05-13 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
US7371721B2 (en) | 2000-09-18 | 2008-05-13 | Sanos Bioscience A/S | Use of GLP-2 and related compounds for the treatment, prevention, diagnosis, and prognosis of bone-related disorders and calcium homeostasis related syndromes |
US7381537B2 (en) | 2003-05-05 | 2008-06-03 | Probiodrug Ag | Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease |
US7462599B2 (en) | 2003-10-15 | 2008-12-09 | Probiodrug Ag | Use of effectors of glutaminyl and glutamate cyclases |
US7608577B2 (en) | 2001-10-12 | 2009-10-27 | Osi Pharmaceuticals, Inc. | Peptidyl ketones as inhibitors of DPIV |
EP2116235A1 (en) | 2005-01-10 | 2009-11-11 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
US7727964B2 (en) | 2001-11-26 | 2010-06-01 | Trustees Of Tufts College | Peptidomimetic inhibitors of post-proline cleaving enzymes |
WO2011005929A1 (en) | 2009-07-09 | 2011-01-13 | Arena Pharmaceuticals, Inc. | Piperidine derivative and its use for the treatment of diabets and obesity |
WO2011127051A1 (en) | 2010-04-06 | 2011-10-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
US8084605B2 (en) | 2006-11-29 | 2011-12-27 | Kelly Ron C | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
WO2012040279A1 (en) | 2010-09-22 | 2012-03-29 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
US8222411B2 (en) | 2005-09-16 | 2012-07-17 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
WO2012135570A1 (en) | 2011-04-01 | 2012-10-04 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145603A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145604A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145361A1 (en) | 2011-04-19 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
US8883714B2 (en) | 2008-04-07 | 2014-11-11 | Arena Pharmaceuticals, Inc. | Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues |
US8906901B2 (en) | 2005-09-14 | 2014-12-09 | Takeda Pharmaceutical Company Limited | Administration of dipeptidyl peptidase inhibitors |
EP2782994A4 (en) * | 2011-11-22 | 2015-07-15 | Tufts College | Small molecule enhancer for dendritic cell cancer vaccines |
US10555929B2 (en) | 2015-03-09 | 2020-02-11 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
US11253508B2 (en) | 2017-04-03 | 2022-02-22 | Coherus Biosciences, Inc. | PPARy agonist for treatment of progressive supranuclear palsy |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1971862B1 (en) | 2006-04-11 | 2010-11-10 | Arena Pharmaceuticals, Inc. | Methods of using gpr119 receptor to identify compounds useful for increasing bone mass in an individual |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991016339A1 (en) * | 1990-04-14 | 1991-10-31 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type iv |
WO1993008259A2 (en) * | 1991-10-22 | 1993-04-29 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type iv |
WO1994003055A1 (en) * | 1992-07-31 | 1994-02-17 | The Government Of The United States Of America, Asrepresented By The Secretary Of The Department Of Health And Human Services | Producing increased numbers of hematopoietic cells by administering inhibitors of dipeptidyl peptidase iv |
WO1995011689A1 (en) * | 1993-10-29 | 1995-05-04 | Trustees Of Tufts College | Use of inhibitors of dipeptidyl-aminopeptidase to block entry of hiv into cells |
WO1995015309A1 (en) * | 1993-12-03 | 1995-06-08 | Ferring B.V. | Dp-iv-serine protease inhibitors |
WO1998025644A1 (en) * | 1996-12-10 | 1998-06-18 | 1149336 Ontario Inc. | Compositions and methods for enhancing intestinal function |
WO1998050046A1 (en) * | 1997-05-07 | 1998-11-12 | Trustees Of Tufts College | Use of cd26 inhibitor for the manufacture of a medicament for the treatment of hiv |
WO1999028474A2 (en) * | 1997-12-01 | 1999-06-10 | The Government Of The United States Of America, Represented By The Secretary Of Health And Human Services | Chemokine variants and methods of use |
WO1999038501A2 (en) * | 1998-02-02 | 1999-08-05 | Trustees Of Tufts College | Method of regulating glucose metabolism, and reagents related thereto |
WO1999062914A1 (en) * | 1998-06-05 | 1999-12-09 | Point Therapeutics, Inc. | Cyclic boroproline compounds |
-
1999
- 1999-08-13 KR KR1020017002162A patent/KR20010079669A/en not_active Application Discontinuation
- 1999-08-13 IL IL14147199A patent/IL141471A0/en unknown
- 1999-08-13 CA CA002339537A patent/CA2339537A1/en not_active Abandoned
- 1999-08-13 WO PCT/US1999/018315 patent/WO2000010549A1/en not_active Application Discontinuation
- 1999-08-13 EP EP99941081A patent/EP1104293A1/en not_active Withdrawn
- 1999-08-13 JP JP2000565871A patent/JP2002523365A/en active Pending
- 1999-08-13 BR BR9913153-6A patent/BR9913153A/en not_active Application Discontinuation
- 1999-08-13 AU AU54801/99A patent/AU5480199A/en not_active Abandoned
-
2001
- 2001-02-19 NO NO20010844A patent/NO20010844L/en not_active Application Discontinuation
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991016339A1 (en) * | 1990-04-14 | 1991-10-31 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type iv |
WO1993008259A2 (en) * | 1991-10-22 | 1993-04-29 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type iv |
WO1994003055A1 (en) * | 1992-07-31 | 1994-02-17 | The Government Of The United States Of America, Asrepresented By The Secretary Of The Department Of Health And Human Services | Producing increased numbers of hematopoietic cells by administering inhibitors of dipeptidyl peptidase iv |
WO1995011689A1 (en) * | 1993-10-29 | 1995-05-04 | Trustees Of Tufts College | Use of inhibitors of dipeptidyl-aminopeptidase to block entry of hiv into cells |
WO1995015309A1 (en) * | 1993-12-03 | 1995-06-08 | Ferring B.V. | Dp-iv-serine protease inhibitors |
WO1998025644A1 (en) * | 1996-12-10 | 1998-06-18 | 1149336 Ontario Inc. | Compositions and methods for enhancing intestinal function |
WO1998050046A1 (en) * | 1997-05-07 | 1998-11-12 | Trustees Of Tufts College | Use of cd26 inhibitor for the manufacture of a medicament for the treatment of hiv |
WO1999028474A2 (en) * | 1997-12-01 | 1999-06-10 | The Government Of The United States Of America, Represented By The Secretary Of Health And Human Services | Chemokine variants and methods of use |
WO1999038501A2 (en) * | 1998-02-02 | 1999-08-05 | Trustees Of Tufts College | Method of regulating glucose metabolism, and reagents related thereto |
WO1999062914A1 (en) * | 1998-06-05 | 1999-12-09 | Point Therapeutics, Inc. | Cyclic boroproline compounds |
Non-Patent Citations (3)
Title |
---|
BRISTOL L A ET AL: "Inhibition of CD26 enzyme activity with pro-boropro stimulates rat granulocyte/macrophage colony formation and thymocyte proliferation in vitro", BLOOD,US,PHILADELPHIA, PA, vol. 85, no. 12, 15 June 1995 (1995-06-15), pages 3602 - 3609, XP002092855, ISSN: 0006-4971 * |
ORAVECZ, TAMAS ET AL: "Regulation of the receptor specificity and function of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted) by dipeptidyl peptidase IV (CD26)-mediated cleavage", J. EXP. MED. (1997), 186(11), 1865-1872, XP000870172 * |
SHIODA, TATSUO ET AL: "Anti-HIV-1 and chemotactic activities of human stromal cell-derived factor 1.alpha. (SDF-1.alpha.) and SDF-1.beta. are abolished by CD26/dipeptidyl peptidase IV-mediated cleavage", PROC. NATL. ACAD. SCI. U. S. A. (1998), 95(11), 6331-6336, XP000867405 * |
Cited By (75)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7459428B2 (en) | 1998-02-02 | 2008-12-02 | Trustees Of Tufts College | Method of regulating glucose metabolism, and reagents related thereto |
US7829530B2 (en) | 1998-02-02 | 2010-11-09 | Trustees Of Tufts College | Method of regulating glucose metabolism, and reagents related thereto |
US7078381B2 (en) | 1998-02-02 | 2006-07-18 | Trustees Of Tufts College | Method of regulating glucose metabolism, and reagents related thereto |
US9044424B2 (en) | 1998-02-02 | 2015-06-02 | 1149336 Ontario, Inc. | Methods of regulating glucose metabolism, and reagents related thereto |
US8513190B2 (en) | 1998-02-02 | 2013-08-20 | Trustees Of Tufts College | Method of regulating glucose metabolism, and reagents related thereto |
US8318669B2 (en) | 1998-02-02 | 2012-11-27 | Trustees Of Tufts College | Method of regulating glucose metabolism, and reagents related thereto |
US7067489B2 (en) | 1998-05-04 | 2006-06-27 | Point Therapeutics, Inc. | Hematopoietic stimulation |
US7166579B2 (en) | 1998-06-24 | 2007-01-23 | Prosidion Limited | Prodrugs of DP IV-inhibitors |
US6979697B1 (en) | 1998-08-21 | 2005-12-27 | Point Therapeutics, Inc. | Regulation of substrate activity |
US6890904B1 (en) | 1999-05-25 | 2005-05-10 | Point Therapeutics, Inc. | Anti-tumor agents |
EP1806138A1 (en) * | 1999-05-25 | 2007-07-11 | Point Therapeutics, Inc. | Anti-tumor agents comprising boroproline compounds |
WO2000071135A1 (en) * | 1999-05-25 | 2000-11-30 | Point Therapeutics, Inc. | Anti-tumor comprising boroproline compounds |
US6949514B2 (en) | 1999-05-25 | 2005-09-27 | Point Therapeutics, Inc. | Anti-tumor agents |
US7335645B2 (en) | 1999-08-24 | 2008-02-26 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV for topical use |
US6949515B2 (en) | 1999-08-24 | 2005-09-27 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV for topical use |
USRE44186E1 (en) | 2000-03-10 | 2013-04-30 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
US6770620B2 (en) | 2000-09-18 | 2004-08-03 | Sanos Bioscience A/S | Use of GLP for the treatment, prevention, diagnosis, and prognosis of bone-related and nutrition-related disorders |
US7371721B2 (en) | 2000-09-18 | 2008-05-13 | Sanos Bioscience A/S | Use of GLP-2 and related compounds for the treatment, prevention, diagnosis, and prognosis of bone-related disorders and calcium homeostasis related syndromes |
WO2002053170A2 (en) | 2001-01-02 | 2002-07-11 | Institut Für Medizintechnologie Magdeburg Gmbh (Imtm) | Combined use of enzyme inhibitors and pharmaceutical preparations thereof for the treatment and prophylaxis of arteriosclerosis, for the treatment and prevention of allergic reactions of type i according to the gell and coombs classification, and for the treatment and prevention of dermatological diseases associated with fo |
US6890905B2 (en) | 2001-04-02 | 2005-05-10 | Prosidion Limited | Methods for improving islet signaling in diabetes mellitus and for its prevention |
WO2003002595A3 (en) * | 2001-06-27 | 2003-05-08 | Probiodrug Ag | Dipeptidyl peptidase iv inhibitors and their uses as anti-cancer agents |
US7109347B2 (en) | 2001-06-27 | 2006-09-19 | Probiodrug Ag | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
WO2003002595A2 (en) * | 2001-06-27 | 2003-01-09 | Probiodrug Ag | Dipeptidyl peptidase iv inhibitors and their uses as anti-cancer agents |
US7368576B2 (en) | 2001-06-27 | 2008-05-06 | Probiodrug Ag | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
US7368421B2 (en) | 2001-06-27 | 2008-05-06 | Probiodrug Ag | Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis |
US6844316B2 (en) | 2001-09-06 | 2005-01-18 | Probiodrug Ag | Inhibitors of dipeptidyl peptidase I |
US7144856B2 (en) | 2001-09-06 | 2006-12-05 | Probiodrug Ag | Inhibitors of dipeptidyl peptidase I |
US7608577B2 (en) | 2001-10-12 | 2009-10-27 | Osi Pharmaceuticals, Inc. | Peptidyl ketones as inhibitors of DPIV |
EP2769715A3 (en) * | 2001-11-26 | 2014-09-17 | Trustees Of Tufts College | Methods for treating autoimmune disorders, and reagents related thereto |
US9757400B2 (en) | 2001-11-26 | 2017-09-12 | Trustees Of Tufts College | Peptidomimetic inhibitors of post-proline cleaving enzymes |
WO2003045228A2 (en) * | 2001-11-26 | 2003-06-05 | Trustees Of Tufts College | Methods for treating autoimmune disorders, and reagents related thereto |
US8410053B2 (en) | 2001-11-26 | 2013-04-02 | Trustees Of Tufts College | Methods for treating autoimmune disorders, and reagents related thereto |
WO2003045228A3 (en) * | 2001-11-26 | 2004-10-21 | Tufts College | Methods for treating autoimmune disorders, and reagents related thereto |
US7727964B2 (en) | 2001-11-26 | 2010-06-01 | Trustees Of Tufts College | Peptidomimetic inhibitors of post-proline cleaving enzymes |
JP2005511636A (en) * | 2001-11-26 | 2005-04-28 | トラスティーズ オブ タフツ カレッジ | Method for treating autoimmune disease and reagent related thereto |
US6946480B2 (en) | 2002-02-28 | 2005-09-20 | Hans-Ulrich Demuth | Glutaminyl based DPIV inhibitors |
WO2003099279A1 (en) * | 2002-05-29 | 2003-12-04 | Novartis Ag | Combination of a dpp iv inhibitor and a cardiovascular compound |
US7381537B2 (en) | 2003-05-05 | 2008-06-03 | Probiodrug Ag | Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease |
US7371871B2 (en) | 2003-05-05 | 2008-05-13 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
CN1292747C (en) * | 2003-09-16 | 2007-01-03 | 广东省心血管病研究所 | Compound formulation for treating hypertension |
US7462599B2 (en) | 2003-10-15 | 2008-12-09 | Probiodrug Ag | Use of effectors of glutaminyl and glutamate cyclases |
WO2005049022A2 (en) * | 2003-11-17 | 2005-06-02 | Novartis Ag | Use of dipeptidyl peptidase iv inhibitors |
EP2839832A3 (en) * | 2003-11-17 | 2015-06-24 | Novartis AG | Use of dipeptidyl peptidase IV inhibitors |
WO2005049022A3 (en) * | 2003-11-17 | 2005-07-21 | Novartis Ag | Use of dipeptidyl peptidase iv inhibitors |
EP2116235A1 (en) | 2005-01-10 | 2009-11-11 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
US8183280B2 (en) | 2005-09-02 | 2012-05-22 | Vantia Limited | FAP inhibitors |
WO2007085895A3 (en) * | 2005-09-02 | 2008-04-17 | Ferring Bv | Fap inhibitors |
WO2007085895A2 (en) * | 2005-09-02 | 2007-08-02 | Ferring B.V. | Fap inhibitors |
US8906901B2 (en) | 2005-09-14 | 2014-12-09 | Takeda Pharmaceutical Company Limited | Administration of dipeptidyl peptidase inhibitors |
US8222411B2 (en) | 2005-09-16 | 2012-07-17 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
WO2007120702A2 (en) | 2006-04-11 | 2007-10-25 | Arena Pharmaceuticals, Inc. | Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto |
EP2253311A2 (en) | 2006-04-11 | 2010-11-24 | Arena Pharmaceuticals, Inc. | Use of GPR119 receptor agonists for increasing bone mass and for treating osteoporosis, as well as combination therapy relating thereto |
US8084605B2 (en) | 2006-11-29 | 2011-12-27 | Kelly Ron C | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
US8883714B2 (en) | 2008-04-07 | 2014-11-11 | Arena Pharmaceuticals, Inc. | Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues |
WO2011005929A1 (en) | 2009-07-09 | 2011-01-13 | Arena Pharmaceuticals, Inc. | Piperidine derivative and its use for the treatment of diabets and obesity |
WO2011127051A1 (en) | 2010-04-06 | 2011-10-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
EP3323818A1 (en) | 2010-09-22 | 2018-05-23 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012040279A1 (en) | 2010-09-22 | 2012-03-29 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012135570A1 (en) | 2011-04-01 | 2012-10-04 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145361A1 (en) | 2011-04-19 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145604A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145603A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
EP2782994A4 (en) * | 2011-11-22 | 2015-07-15 | Tufts College | Small molecule enhancer for dendritic cell cancer vaccines |
CN106075450A (en) * | 2011-11-22 | 2016-11-09 | 塔夫茨大学信托人 | Little molecule reinforcing agent for dendritic cell cancer vaccine |
EP3106173A1 (en) * | 2011-11-22 | 2016-12-21 | Trustees Of Tufts College | Small molecule enhancer for dendritic cell cancer vaccines |
US9284337B2 (en) | 2011-11-22 | 2016-03-15 | Trustees Of Tufts College | Small molecule enhancer for dendritic cell cancer vaccines |
US9839646B2 (en) | 2011-11-22 | 2017-12-12 | Trustees Of Tufts College | Small molecule enhancer for dendritic cell cancer vaccines |
WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
US10555929B2 (en) | 2015-03-09 | 2020-02-11 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
US10772865B2 (en) | 2015-03-09 | 2020-09-15 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
US11400072B2 (en) | 2015-03-09 | 2022-08-02 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
US11253508B2 (en) | 2017-04-03 | 2022-02-22 | Coherus Biosciences, Inc. | PPARy agonist for treatment of progressive supranuclear palsy |
Also Published As
Publication number | Publication date |
---|---|
NO20010844L (en) | 2001-04-23 |
CA2339537A1 (en) | 2000-03-02 |
BR9913153A (en) | 2001-05-15 |
IL141471A0 (en) | 2002-03-10 |
EP1104293A1 (en) | 2001-06-06 |
JP2002523365A (en) | 2002-07-30 |
AU5480199A (en) | 2000-03-14 |
KR20010079669A (en) | 2001-08-22 |
NO20010844D0 (en) | 2001-02-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1104293A1 (en) | Regulation of substrate activity | |
US7265118B2 (en) | Regulation of substrate activity | |
US6355614B1 (en) | Cyclic boroproline compounds | |
US6100234A (en) | Treatment of HIV | |
US6368788B1 (en) | Method of treating complications in immunodepressed states resulting from HIV infection | |
US5965532A (en) | Multivalent compounds for crosslinking receptors and uses thereof | |
US5770576A (en) | Pharmaceutical dipeptide compositions and methods of use thereof: systemic toxicity | |
EP0914123A1 (en) | Prodrugs of thalidomide and methods for using same as modulators of t-cell function | |
US20140024588A1 (en) | Method for inducing sustained immune response | |
JP2004026678A (en) | Therapeutic agent for type 2 diabetes | |
US5753628A (en) | Peptide inhibitors of TNF containing predominantly D-amino acids | |
US5811399A (en) | Pharmaceutical dipeptide compositions and methods of use thereof: immunodepressants | |
US5807830A (en) | Method for treatment of purulent inflammatory diseases | |
JP2018509380A (en) | N- (4-hydroxy-4-methyl-cyclohexyl) -4-phenyl-benzenesulfonamide compound and N- (4-hydroxy-4-methyl-cyclohexyl) -4- (2-pyridyl)- Benzenesulfonamide compounds and their therapeutic use | |
MXPA01001635A (en) | Regulation of substrate activity | |
US5641751A (en) | Tumor necrosis factor inhibitors | |
US6107273A (en) | Tumor necrosis factor inhibitors | |
JPH07507061A (en) | Peptide T and related peptides in the treatment of inflammation including multiple sclerosis | |
US20050164312A1 (en) | IL1-beta: a new target for myeloma therapy | |
Myhre | Gram-positive endotoxemia and modulation of the innate immune response | |
WO2000067736A2 (en) | Therapeutic use of an inhibitor or an antagonist of an abc protein in bone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2339537 Country of ref document: CA Ref country code: CA Ref document number: 2339537 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 54801/99 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 509866 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2001/001635 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 141471 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020017002162 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1999941081 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09744658 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 1999941081 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 1020017002162 Country of ref document: KR |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1999941081 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1020017002162 Country of ref document: KR |