Inhibitors of proline-specific dipeptidyl peptidases: DPP IV inhibitors as a novel approach for the treatment of type 2 diabetes

Expert Opinion on Therapeutic Patents

Volumn 15, Issue 10, 2005, Pages 1387-1407

  Augustyns, Koen ^a   Van der Veken, Pieter ^a   Haemers, Achiel ^a  

^a UNIVERSITY OF ANTWERP   (Belgium)

Author keywords

Dipeptidyl peptidase IV (DPP IV); DPP II; DPP8; DPP9; FAP ; Medicinal chemistry; Type 2 diabetes

Indexed keywords

1 [4 METHYL 1 (2 PYRIMIDINYL) 4 PIPERIDYLAMINOACETYL] 2 PYRROLIDINECARBONITRILE; 4' FLUOROBIPHENYL DERIVATIVE; 7 BENZYL 1,3 DIMETHYL 8 (1 PIPERAZINYL)XANTHINE; AMINOMETHYLPYRIMIDINE; ANTIDIABETIC AGENT; BETA METHYLPHENYLALANINE THIAZOLIDIDE; CYCLOHEXYLGLYCINE DERIVATIVE; CYCLOHEXYLGLYCINE PYRROLIDIDE; DIPEPTIDYL PEPTIDASE; DIPEPTIDYL PEPTIDASE II; DIPEPTIDYL PEPTIDASE IV; DIPEPTIDYL PEPTIDASE IV INHIBITOR; DIPEPTIDYL PEPTIDASE IX; DIPEPTIDYL PEPTIDASE VIII; DPP 728; FE 999011; GLIBENCLAMIDE; GSK 23A; ISOLEUCYLTHIAZOLIDIDE; PROLYLPROLINE DI(4 ACETYLAMINOPHENYL)PHOSPHONATE; PYRROLIDINE DERIVATIVE; SAXAGLIPTIN; SEPRASE; SITAGLIPTIN; SULFOSTIN; TALABOSTAT; THIAZOLIDINE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALYLBOROPROLINE; VALYLPYRROLIDIDE; VILDAGLIPTIN;

CHEMISTRY; CLINICAL TRIAL; DRUG ABSORPTION; DRUG CLEARANCE; DRUG DESIGN; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENCY; DRUG SELECTIVITY; DRUG STABILITY; DRUG TOXICITY; ENZYME INHIBITION; ENZYME SPECIFICITY; HUMAN; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PATENT; PROTEIN TARGETING; PUBLISHING; REVIEW; SCIENTIFIC LITERATURE; STRUCTURE ACTIVITY RELATION;

EID: 27744590673     PISSN: 13543776     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543776.15.10.1387     Document Type: Review

References (111)

1. AUGUSTYNS K, VAN DER VEKEN P, SENTEN K, HAEMERS A: Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of Type 2 diabetes. Expert Opin. Ther. Patents (2003) 13:499-510.
2. AUGUSTYNS K, BAL G, THONUS G et al.: The unique properties of dipeptidyl-peptidase IV (DPP IV/CD26) and the therapeutic potential of DPP IV inhibitors. Curr. Med. Chem. (1999) 6:311-327.
3. AUGUSTYNS K, VAN DER VEKEN P, SENTEN K, HAEMERS A: The therapeutic potential of inhibitors of dipeptidyl peptidase IV (DPP IV) and related proline-specific dipeptidyl aminopeptidases. Curr. Med. Chem. (2005) 12:971-998.
4. LAMBEIR AM, DURINX C, SCHARPE S, DE MEESTER I: Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit. Rev. Clin. Lab. Sci. (2003) 40:209-294.
5. AHREN B: Inhibition of dipeptidyl peptidase-4 (DPP4) - A novel approach to treat Type 2 diabetes. Curr. Enzyme Inhib. (2005) 1:65-73.
6. DEACON CF: Therapeutic strategies based on glucagon-like peptide 1. Diabetes (2004) 53:2181-2189.
7. DEACON CF, AHREN B, HOLST JJ: Inhibitors of dipeptidyl peptidase IV: a novel approach for the prevention and treatment of Type 2 diabetes? Expert Opin. Investig. Drugs (2004) 13:1091-1102.
8. HOLST JJ, DEACON CF: Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of Type 2 diabetes mellitus. Curr. Opin. Pharmacol. (2004) 4:589-596.
9. HOLST JJ: Treatment of Type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP IV inhibitors. Expert Opin. Emerg. Drugs (2004) 9:155-166.
10. WEBER AE: Dipeptidyl peptidase IV. inhibitors for the treatment of diabetes. J. Med. Chem. (2004) 47:4135-4141.
11. NAUCK MA, STOCKMANN F, EBERT R, CREUTZFELDT W: Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes. Diabetologia (1986) 29:46-52.
12. NAUCK MA, KLEINE N, ORSKOV C et al.: Normalization of fasting hyperglycemia by exogenous GLP-1 (7-36 amide) in Type 2 diabetic patients. Diabetologia (2005) 36:741-744.
13. PAULY RP, DEMUTH HU, ROSCHE F et al.: Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor Ile-thiazolidide. Metabolism (1999) 48:385-389.
14. PEDERSON RA, WHITE HA, SCHLENZIG D et al.: Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide. Diabetes (1998) 47:1253-1258.
15. POSPISILIK JA, STAFFORD SG, DEMUTH HU et al.: Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and β-cell glucose responsiveness in VDF (fa/fa) Zucker rats. Diabetes (2002) 51:943-950.
16. POSPISILIK JA, STAFFORD SG, DEMUTH HU, MCINTOSH CH, PEDERSON RA: Long-term treatment with dipeptidyl peptidase IV inhibitor improves hepatic and peripheral insulin sensitivity in the VDF Zucker rat: a euglycemic-hyperinsulinemic clamp study. Diabetes (2002) 51:2677-2683.
17. POSPISILIK JA, MARTIN J, DOTY T et al.: Dipeptidyl peptidase IV inhibitor treatment stimulates β-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes (2003) 52:741-750.
18. DEACON CF, HUGHES TE, HOLST JJ: Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig. Diabetes (1998) 47:764-769.
19. DEACON CF, DANIELSEN P, KLARSKOV L, OLESEN M, HOLST JJ: Dipeptidyl peptidase IV inhibition reduces the degradation and clearance of GIP and potentiates its insulinotropic and antihyperglycemic effects in anesthetized pigs. Diabetes (2001) 50:1588-1597.
20. AHREN B, HOLST JJ, MARTENSSON H, BALKAN B: Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice. Eur. J. Pharmacol. (2000) 404:239-245.
21. SUDRE B, BROQUA P, WHITE RB et al.: Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male zucker diabetic fatty rats. Diabetes (2002) 51:1461-1469.
22. BALKAN B, KWASNIK L, MISERENDINO R, HOLST JJ, LI X: Inhibition of dipeptidyl peptidase IV with NVP-DPP728 increases plasma GLP-1 (7-36 amide) concentrations and improves oral glucose tolerance in obese Zucker rats. Diabetologia (1999) 42:1324-1331.
23. AHREN B, SIMONSSON E, LARSSON H et al.: Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in Type 2 diabetes. Diabetes Care (2002) 25:869-875.
24. DEACON CF, WAMBERG S, BIE P, HUGHES TE, HOLST JJ: Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs. J. Endocrinol. (2002) 172:355-362.
25. REIMER MK, HOLST JJ, AHREN B: Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice. Eur. J. Endocrinol. (2002) 146:717-727.
26. MITANI H, TAKIMOTO M, HUGHES TE, KIMURA M: Dipeptidyl peptidase IV inhibition improves impaired glucose tolerance in high-fat diet-fed rats: study using a Fischer 344 rat substrain deficient in its enzyme activity. Jpn. J. Pharmacol. (2002) 88:442-450.
27. MITANI H, TAKIMOTO M, KIMURA M: Dipeptidyl peptidase IV inhibitor NVP-DPP728 ameliorates early insulin response and glucose tolerance in aged rats but not in aged Fischer 344 rats lacking its enzyme activity. Jpn. J. Pharmacol. (2002) 88:451-458.
28. LANKAS G, LEITING B, ROY RS et al.: Inhibition of DPP8/9 results in toxicity in preclinical species: potential importance of selective dipeptidyl peptidase IV inhibition for the treatment of Type 2 diabetes mellitus. Diabetes (2004) 53:A2,7-OR.
29. HUGHES TE, MONE MD, RUSSELL ME, WELDON SC, VILLHAUER EB: NVP-DPP728 (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl] amino]acetyl]-2-cyano-(S)-pyrrolidine), a slow-binding inhibitor of dipeptidyl peptidase IV. Biochemistry (1999) 38:11597-11603.
30. ENGEL M, HOFFMANN T, WAGNER L et al.: The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism. Proc. Natl. Acad. Sci. USA (2003) 100:5063-5068.
31. FLENTKE GR, MUNOZ E, HUBER BT 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. Proc. Natl. Acad. Sci. USA (1991) 88:1556-1559.
32. BELYAEV A, ZHANG X, AUGUSTYNS K et al.: Structure-activity relationship of diaryl phosphonate esters as potent irreversible dipeptidyl peptidase IV inhibitors. J. Med. Chem. (1999) 42:1041-1052.
33. MAGNIN DR, ROBL JA, SULSKY RB et al.: Synthesis of novel potent dipeptidyl peptidase IV inhibitors with enhanced chemical stability: interplay between the N-terminal amino acid alkyl side chain and the cyclopropyl group of α-aminoacyl-1-cis-4,5-methanoprolinenitrile-based inhibitors. J. Med. Chem. (2004) 47:2587-2598.
34. VAN DER VEKEN P, SENTEN K, KERTESZ I et al.: Fluoro-olefins as peptidomimetic inhibitors of dipeptidyl peptidases. J. Med. Chem. (2005) 48:1768-1780.
35. ASHWORTH D, ATRASH B, BAKER GR et al.: 2-Cyanopyrrolidides as potent, stable inhibitors of dipeptidyl peptidase IV. Bioorg. Med. Chem. Lett. (1996) 6:1163-1166.
36. PARMEE ER, HE J, MASTRACCHIO A et al.: 4-Amino cyclohexylglycine analogues as potent dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. (2004) 14:43-46.
37. ASHTON WT, DONG H, SISCO RM et al.: Diastereoselective synthesis and configuration-dependent activity of (3-substituted-cycloalkyl)glycine pyrrolidides and thiazolidides as dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. (2004) 14:859-863.
38. AUGUSTYNS KJL, LAMBEIR AM, BORLOO M et al.: Pyrrolidides: synthesis and structure-activity relationship as inhibitors of dipeptidyl peptidase IV. Eur. J. Med. Chem. (1997) 32:301-309.
39. CALDWELL CG, CHEN P, HE J et al.: Fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. (2004) 14:1265-1268.
40. XU S, ZHU B, TEFFERA Y et al.: Metabolic activation of fluoropyrrolidine dipeptidyl peptidase-IV inhibitors by rat liver microsomes. Drug. Metab. Dispos. (2005) 33:121-130.
41. XU J, WEI L, MATHVINK R et al.: Discovery of potent and selective phenylalanine based dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. (2005) 15:2533-2536.
42. MASTRACCHIO A, PARMEE ER, LEITING B et al.: Heterocycle fused cyclohexylglycine derivatives as novel dipeptidyl peptidase-IV inhibitors. Heterocycles (2004) 62:203-206.
43. EDMONDSON SD, MASTRACCHIO A, DUFFY JL et al.: Discovery of potent and selective orally bioavailable β-substituted phenylalanine derived dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. (2005) 15 online.
44. XU J, OK HO, GONZALEZ EJ et al.: Discovery of potent and selective β-homophenylalanine based dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. (2004) 14:4759-4762.
45. EDMONDSON SD, MASTRACCHIO A, BECONI M et al.: Potent and selective proline derived dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. (2004) 14:5151-5155.
46. BROCKUNIER LL, HE J, COLWELL LF et al.: Substituted piperazines as novel dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. (2004) 14:4763-4766.
47. KIM D, WANG L, BECONI M et al.: (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl]-1- (2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of Type 2 diabetes. J. Med. Chem. (2005) 48:141-151.
48. ASHTON WT, SISCO RM, DONG H et al.: Dipeptidyl peptidase IV inhibitors derived from β-aminoacylpiperidines bearing a fused thiazole, oxazole, isoxazole or pyrazole. Bioorg. Med. Chem. Lett. (2005) 15:2253-2258.
49. FUKUSHIMA H, HIRATATE A, TAKAHASHI M et al.: Synthesis and structure-activity relationships of potent 3-or 4-substituted-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. (2004) 12:6053-6061.
50. HAFFNER C: 4-Fluorocyanopyrrolidines as inhibitors of dipeptidyl peptidase IV (DPP IV). 228th ACS Meeting. Philadelphia, PA. (2004). Abstract 205.
51. AHN JH, KIM HM, JUNG SH et al.: Synthesis and DP-IV inhibition of cyanopyrazoline derivatives as potent anti-diabetic agents. Bioorg. Med. Chem. Lett. (2004) 14:4461-4465.
52. AHN JH, KIM JA, KIM HM et al.: Synthesis and evaluation of pyrazolidine derivatives as dipeptidyl peptidase IV (DPP IV) inhibitors. Bioorg. Med. Chem. Lett. (2005) 15:1337-1340.
53. CHEON HG, KIM SS, KIM S et al.: Inhibition of dipeptidyl peptidase IV by novel inhibitors with pyrazolidine scaffold. Biochem. Pharmacol. (2005) online.
54. VILLHAUER EB, BRINKMAN JA, NADERI GB et al.: 1-[2-[(5-Cyanopyridin-2-yl)amino]ethylamino] acetyl-2-(S)-pyrrolidinecarbonitrile: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem. (2002) 45:2362-2365.
55. VILLHAUER EB, BRINKMAN JA, NADERI GB et al.: 1-[[(3-hydroxy-1-adamantyl)amino]acetyl] -2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem. (2003) 46:2774-2789.
56. TAKASAKI K, IWASE M, NAKAJIMA T et al.: K579, a slow-binding inhibitor of dipeptidyl peptidase IV, is a long-acting hypoglycemic agent. Eur. J. Pharmacol. (2004) 486:335-342.
57. TAKASAKI K, TAKADA H, NAKAJIMA T et al.: Involvement of the active metabolites in the inhibitory activity of K579 on rat plasma dipeptidyl peptidase IV. Eur. J. Pharmacol. (2004) 505:237-241.
58. TAKASAKI K, NAKAJIMA T, UENO K, NOMOTO Y, HIGO K: Effects of combination treatment with dipeptidyl peptidase IV inhibitor and sulfonylurea on glucose levels in rats. J. Pharmacol. Sci. (2004) 95:291-293.
59. SAKASHITA H, KITAJIMA H, NAKAMURA M, AKAHOSHI F, HAYASHI Y: 1-((S)-γ-substituted prolyl)-(S-2-cyanopyrrolidine as a novel series of highly potent DPP IV inhibitors. Bioorg. Med. Chem. Lett. (2005) 15:2441-2445.
60. KANSTRUP AB, BRANNER S, CARR RD et al.: Understanding the structure of human DPP IV and its specificity. 3rd International Protease Meeting. Nagoya, Japan. (2003). Poster.
61. KANSTRUP AB, BOWLER AN, CARR RD et al.: β-amino acid based inhibitors of DPP IV. International Symposium on Medicinal Chemistry. Copenhagen, Denmark. (2004). Poster.
62. HAMANN LG: Design, synthesis and pharmacology of BMS-477118: a long acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of Type 2 diabetes. 228th ACS Meeting. Philadelphia, PA, USA (2004). OR-207.
63. ROBL JA: Design, synthesis, and pharmacology of BMS-477118: a long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of Type 2 diabetes. 18th International Symposium on Medicinal Chemistry. Copenhagen, Denmark. (2004). Oral communication.
64. ZHAO K, LIM DS, FUNAKI T, WELCH JT: Inhibition of dipeptidyl peptidase IV (DPP IV) by 2-(2-amino-1-fluoro-propylidene) -cyclopentanecarbonitrile, a fluoroolefin containing peptidomimetic. Bioorg. Med. Chem. (2003) 11:207-215.
65. VAN DER VEKEN P, KERTESZ I, SENTEN K, HAEMERS A, AUGUSTYNS K: Synthesis of (E)- and (Z)-fluoro-olefin analogues of potent dipeptidyl peptidase IV inhibitors. Tetrahedron Lett. (2003) 44:6231-6234.
66. FERRARIS D, KO YS, CALVIN D et al.: Ketopyrrolidines and ketoazetidines as potent dipeptidyl peptidase IV (DPP IV) inhibitors. Bioorg. Med. Chem. Lett. (2004) 14:5579-5583.
67. KANSTRUP AB, BJELKE JR, BOWLER AN et al.: Design, synthesis, and biological evaluation of a series of potent xanthine-based inhibitors of the enzyme DPP IV. 2nd International Conference on Dipeptidyl Aminopeptidases. Magdeburg, Germany. (2005). Poster.
68. PETERS JU, WEBER S, KRITTER S et al.: Aminomethylpyrimidines as novel DPP IV inhibitors: a 10(5)-fold activity increase by optimization of aromatic substituents. Bioorg. Med. Chem. Lett. (2004) 14:1491-1493.
69. PETERS JU, HUNZIKER D, FISCHER H et al.: An aminomethylpyrimidine DPP IV inhibitor with improved properties. Bioorg. Med. Chem. Lett. (2004) 14:3575-3578.
70. PETERS JU, WEBER S, KRITTER S et al.: Aminomethylpyridines as DPP IV inhibitors. Bioorg. Med. Chem. Lett. (2004) 14:3579-3580.
71. AKIYAMA T, ABE M, HARADA S et al.: Sulphostin, a potent inhibitor for dipeptidyl peptidase IV from Streptomyces sp. MK251-43F3. J. Antibiot. (Tokyo) (2001) 54:744-746.
72. ABE M, AKIYAMA T, NAKAMURA H et al.: First synthesis and determination of the absolute configuration of sulphostin, a novel inhibitor of dipeptidyl peptidase IV. J. Nat. Prod. (2004) 67:999-1004.
73. ABE M, AKIYAMA T, UMEZAWA Y et al.: Synthesis and biological activity of sulphostin analogues, novel dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. (2005) 13:785-797.
74. ABE M, ABE F, NISHIMURA C et al.: Sulphostin, a novel inhibitor of dipeptidyl peptidase IV (DPP IV) that stimulates hematopoiesis in mice. J. Antibiot. (Tokyo) (2005) 58:111-117.
75. JONES B, ADAMS S, MILLER GT et al.: Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies. Blood (2003) 102:1641-1648.
76. CHEN WT, KELLY T: Seprase complexes in cellular invasiveness. Cancer Metastasis Rev. (2003) 22:259-269.
77. KELLY T: Fibroblast activation protein-α and dipeptidyl peptidase IV (CD26): cell-surface proteases that activate cell signaling and are potential targets for cancer therapy. Drug Resistance Updates (2005) 8:51-58.
78. CHENG JD, DUNBRACK RL, VALIANOU M et al.: Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Res. (2002) 62:4767-4772.
79. GOODMAN JD, ROZYPAL TL, KELLY T: Seprase, a membrane-bound protease, alleviates the serum growth requirement of human breast cancer cells. Clin. Exp. Metastasis (2003) 20:459-470.
80. HUANG Y, WANG S, KELLY T: Seprase promotes rapid tumor growth and increased microvessel density in a mouse model of human breast cancer. Cancer Res. (2004) 64:2712-2716.
81. AIMES RT, ZIJLSTRA A, HOOPER JD et al.: Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis. Thromb. Haemost. (2003) 89:561-572.
82. CHENG JD, VALIANOU M, CANUTESCU AA et al.: Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth. Mol. Cancer Ther. (2005) 4:351-360.
83. RAMIREZ-MONTAGUT T, BLACHERE NE, SVIDERSKAYA EV et al.: FAPα, a surface peptidase expressed during wound healing, is a tumor suppressor. Oncogene (2004) 23:5435-5446.
84. COLLINS PJ, MCMAHON G, O'BRIEN P, O'CONNOR B: Purification, identification and characterisation of seprase from bovine serum. Int. J. Biochem. Cell. Biol. (2004) 36:2320-2333.
85. LAI JH, LIU Y, MAW HH et al.: Investigation of exo- and endopeptidase activity of fibroblast activation protein inhibitors. 2nd International Conference on Dipeptidyl Aminopeptidases. Magdeburg, Germany. (2005). Poster A60.
86. AERTGEERTS K, LEVIN I, SHI L et al.: Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein-α. J. Biol. Chem. (2005) 280:19441-19444.
87. ADAMS S, MILLER GT, JESSON MI et al.: PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. (2004) 64:5471-5480.
88. MCINTYRE JA, CASTANER J: Talabostat. Oncolytic, hematopoietic agent, dipeptidyl-peptidase IV (CD26) inhibitor, fibroblast activation protein inhibitor. Drugs Fut. (2004) 29:882-886.
89. CHIRAVURI M, SCHMITZ T, YARDLEY K et al.: A novel apoptotic pathway in quiescent lymphocytes identified by inhibition of a post-proline cleaving aminodipeptidase: a candidate target protease, quiescent cell proline dipeptidase. J. Immunol. (1999) 163:3092-3099.
90. CHEN T, AJAMI K, MCCAUGHAN GW, GORRELL MD, ABBOTT CA: Dipeptidyl peptidase IV gene family. The DPIV family. Adv. Exp. Med. Biol. (2003) 524:79-86.
91. ABBOTT CA, YU DM: WOOLLATT E et al.: Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8. Eur. J. Biochem. (2000) 267:6140-6150.
92. CHEN YS, CHIEN CH, GOPARAJU CM et al.: Purification and characterization of human prolyl dipeptidase DPP8 in Sf9 insect cells. Protein Expr. Purif. (2004) 35:142-146.
93. OLSEN C, WAGTMANN N: Identification and characterization of human DPP9, a novel homologue of dipeptidyl peptidase IV. Gene (2002) 299:185-193.
94. QI SY, RIVIERE PJ, TROJNAR J, JUNIEN JL, AKINSANYA KO: Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases. Biochem. J. (2003) 373:179-189.
95. AJAMI K, ABBOTT CA, MCCAUGHAN GW, GORRELL MD: Dipeptidyl peptidase 9 has two forms, a broad tissue distribution, cytoplasmic localization and DPIV-like peptidase activity. Biochim. Biophys. Acta (2004) 1679:18-28.
96. LEITING B, NICHOLS E, BIFTU T et al.: Inhibition of dipeptidyl peptidase IV does not attenuate T cell activation in vitro. Diabetes (2004) 53:A2,6-OR.
97. JIAANG WT, CHEN YS, HSU T et al.: Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8. Bioorg. Med. Chem. Lett. (2005) 15:687-691.
98. LEITING B, PRYOR KD, WU JK et al.: Catalytic properties and inhibition of proline-specific dipeptidyl peptidases II, IV and VII. Biochem. J. (2003) 371:525-532.
99. MAES MB, LAMBEIR AM, GILANY K et al.: Kinetic investigation of human dipeptidyl peptidase II (DPP II)-mediated hydrolysis of dipeptide derivatives and its identification as quiescent cell proline dipeptidase (QPP)/dipeptidyl peptidase 7 (DPP7). Biochem. J. (2005) 386:315-324.
100. UNDERWOOD R, CHIRAVURI M, LEE H et al.: Sequence, purification, and cloning of an intracellular serine protease, quiescent cell proline dipeptidase. J. Biol. Chem. (1999) 274:34053-34058.
101. CHIRAVURI M, LEE H, MATHIEU SL, HUBER BT: Homodimerization via a leucine zipper motif is required for enzymatic activity of quiescent cell proline dipeptidase. J. Biol. Chem. (2000) 275:26994-26999.
102. CHIRAVURI M, AGARRABERES F, MATHIEU SL, LEE H, HUBER BT: Vesicular localization and characterization of a novel post-proline-cleaving aminodipeptidase, quiescent cell proline dipeptidase. J. Immunol. (2000) 165:5695-5702.
103. CHIRAVURI M, HUBER BT: Aminodipeptidase inhibitor-induced cell death in quiescent lymphocytes: a review. Apoptosis (2000) 5:319-322.
104. SENTEN K, VAN DER VEKEN P, BAL G et al.: Development of potent and selective dipeptidyl peptidase II inhibitors. Bioorg. Med. Chem. Lett. (2002) 12:2825-2828.
105. SENTEN K, VAN DER VEKEN P, DE MEESTER I et al.: Design, synthesis, and SAR of potent and selective dipeptide-derived inhibitors for dipeptidyl peptidases. J. Med. Chem. (2003) 46:5005-5014.
106. SENTEN K, VAN DER VEKEN P, DE MEESTER I et al.: γ-Amino-substituted analogues of 1-[(S)-2,4-diaminobutanoyl]piperidine as highly potent and selective dipeptidyl peptidase II inhibitors. J. Med. Chem. (2004) 47:2906-2916.
107. SENTEN K, DANIELS L, VAN DER VEKEN P et al.: Rapid parallel synthesis of dipeptide diphenyl phosphonate esters as inhibitors of dipeptidyl peptidases. J. Comb. Chem. (2003) 5:336-344.
108. AHREN B, LANDIN-OLSSON M, JANSSON PA et al.: Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in Type 2 diabetes. J. Clin. Endocrinol. Metab. (2004) 89:2078-2084.
109. AHREN B, GOMIS R, STANDL E, MILLS D, SCHWEIZER A: 12- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with Type 2 diabetes. Diabetes Care (2004) 27:2874-2880.
110. SCOTT R, HERMAN G, ZHAO P et al.: Twelve-week efficacy and tolerability of MK-0431, a dipeptidyl peptidase IV (DPP IV) inhibitor, in the treatment of Type 2 diabetes (T2D). 65th American Diabetes Association Annual Meeting. San Diego, USA. (2005). 41-OR.
111. WEBER AE, KIM D, BECONI M et al.: MK-0431 is a potent, selective, dipeptidyl peptidase IV inhibitor for the treatment of Type 2 diabetes. 63rd American Diabetes Association Annual Meeting. Orlando, FL, USA (2004). 633-P.