Inhibitors of Dipeptidyl Peptidase IV - Recent advances and structural views

Current Topics in Medicinal Chemistry

Volumn 5, Issue 16, 2005, Pages 1623-1637

  Hunziker, Daniel ^a   Hennig, Michael ^a   Peters, Jens Uwe ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

3 AMINO 1 [5,6,7,8 TETRAHYDRO 3 (TRIFLUOROMETHYL) 1,2,4 TRIAZOLO[4,3 A]PYRAZIN 7 YL] 4 (2,4,5 TRIFLUOROPHENYL) 1 BUTANONE; 6 [[2 [[2 (2 CYANO 1 PYRROLIDINYL) 2 OXOETHYL]AMINO]ETHYL]AMINO]NICOTINONITRILE; ANTIDIABETIC AGENT; DIPEPTIDYL PEPTIDASE IV; DIPEPTIDYL PEPTIDASE IV INHIBITOR; DIPROTIN A; FE 999011; GLIPIZIDE; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 DERIVATIVE; GLUCOSE; INSULIN; ISOLEUCINE THIAZOLIDIDE; METFORMIN; PLACEBO; PRODRUG; PSN 9301; PYRIMIDINE DERIVATIVE; QUINAZOLINONE DERIVATIVE; QUINOLIZINE DERIVATIVE; QUINOLONE DERIVATIVE; SAXAGLIPTIN; TRIAZOLE DERIVATIVE; UNCLASSIFIED DRUG; VILDAGLIPTIN; XANTHINE DERIVATIVE;

BODY WEIGHT DISORDER; CLINICAL PROTOCOL; CLINICAL TRIAL; CYCLIZATION; DISEASE SEVERITY; DRUG ACTIVITY; DRUG DOSE REGIMEN; DRUG EFFICACY; DRUG HALF LIFE; DRUG RESEARCH; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TOLERABILITY; GASTROINTESTINAL SYMPTOM; HORMONE ACTION; HUMAN; HYPOGLYCEMIA; IC 50; IN VIVO STUDY; MONOTHERAPY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; REVIEW; WEIGHT GAIN;

ANTIGENS, CD26; MOLECULAR MIMICRY; MOLECULAR STRUCTURE; PROTEASE INHIBITORS; X-RAY DIFFRACTION;

EID: 33644892053     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802605775009685     Document Type: Review

References (129)

1. DeFronzo, R. Pharmacologic therapy for type 2 diabetes mellitus. Ann. Intern. Med. 1999, 131(4), 281-303.
2. Stern, M. P.; Gonzalez, C.; Mitchell, B. D.; Villalpando, E.; Haffner, S. M.; Hazuda, H. P. Genetic and environmental determination of type 2 diabetes in Mexico City and San Antonio. Diabetes 1992, 41, 484-292.
3. Chu-Moyer, M. Y. Patent focus on antidiabetic agents. Expert. Opin. Ther. Patents 2000, 10(6), 787-801.
4. Skyler, J. S. Diabetes mellitus: pathogenesis and treatment strategies. J. Med. Chem. 2004, 47, 4113-4117.
5. Rotella, D. P. Novel "second-generation" approaches for the control of type 2 diabetes. J. Med. Chem. 2004, 47(17), 4111-4112.
6. Henke, B. R. Peroxisome proliferator-activated receptor α/μ dual agonists for the treatment of type 2 diabetes. J. Med. Chem. 2004, 47(17), 4118-4127.
7. Knudsen, L. B. Glucagon-like peptide-1: The basis of a new class of treatment for type 2 diabetes. J. Med. Chem. 2004, 47(17), 4128-4134.
8. Van Huijsduijnen, R. H.; Sauer, W. H. B.; Bombrun, A.; Swinnen, D. Prospects for inhibitors of protein tyrosin phosphatase 1B as antidiabetic drugs. J. Med. Chem. 2004, 47(17), 4142-4146.
9. Drucker, J. D. Enhancing Incretin action for the treatment of type 2 diabetes. Diabetes Care 2003, 26(10), 2929-2940.
10. Vahl, T. P.; D'Alessio, D. A. Gut peptides in the treatment of diabetes mellitus. Expert Opin. Invest. Drugs 2004, 13(3), 177-188.
11. Meier, J. J.; Gallwitz, B.; Nauck, M. A. Glucagon-like peptide 1 and gastric inhibitory polypeptide: potential applications in type 2 diabetes mellitus. BioDrugs 2003, 17(2), 93-102.
12. Holst, J. J.; Deacon, C. F. Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of type 2 diabetes mellitus. Curr. Opin. Pharmacol. 2004, 4(6), 589-596.
13. Edwards, C. M. B. GLP-1: target for a new class of antidiabetic agents? J. R. Soc. Med. 2004, 97(6), 270-274.
14. Holst, J. J. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab. Res. Rev. 2002, 18(6), 430-441.
15. Nauck, M. A. Glucagon-like peptide 1 (GLP-1) in the treatment of diabetes. Horm. Met. Res. 2004, 36(11/12), 852-858.
16. Huang, A.; Raskin, P. Glucagon-like peptide: The time is near. Basic Clin. Pharmacol. Toxicol. 2004, 95(6), 249-251.
17. Holst, J. J.; Orskov, C. The incretin approach for diabetes treatment. Modulation of islet hormone release by GLP-1 agonism. Diabetes 2004, 53(Suppl. 3), 197-204.
18. Deacon, C. F. Therapeutic strategies based on glucagon-like peptide 1. Diabetes 2004, 53(9), 2181-2189.
19. Rachman, J.; Barrow, B. A.; Levy, J. C.; Turner, R. C. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia 1997, 40(2), 205-211.
20. Mentlein, R. Therapeutic assessment of glucagon-like peptide-1 agonists compared with dipeptidyl peptidase IV inhibitors as potential antidiabetic drugs. Expert Opin. Investig. Drugs 2005, 14(1), 57-64.
21. Mentlein, R.; Gallwitz, B.; Schmidt, E. Dipeptidyl-peptidase IV hydrolyzes gastric inhibitory polypeptide, glucagon-like peptide-1 (7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur. J. Biochem. 1993, 214, 829.
22. Deacon, C. F.; Ahren, B.; Holst, J. J. Inhibitors of dipeptidyl peptidase IV: A novel approach for the prevention and treatment of type 2 diabetes? Expert Opin. Invest. Drugs 2004, 13(9), 1091-1102.
23. Weber, A. E. Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. J. Med. Chem. 2004, 47(17), 4135-4141.
24. Holst, J. J. Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors. Expert Opin. Emerging Drugs 2004, 9(1), 155-166.
25. Wiedeman, P. E.; Trevillyan, J. M. Dipeptidyl peptidase IV inhibitors for the treatment of impaired glucose tolerance and type 2 diabetes. Curr. Opin. Invest. Drugs 2003, 4(4), 412-420.
26. 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. Pat. 2003, 13(4), 499-510.
27. Drucker, D. J. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin. Invest. Drugs 2003, 12(1), 87-100.
28. Deacon, C. F.; Holst, J. J. Dipeptidyl peptidase IV inhibition as an approach to the treatment and prevention of type 2 diabetes: a historical perspective. Biochem. Biophys. Res. Commun. 2002, 294(1), 1-4.
29. Vilsboll, T.; Krarup, T.; Madsbad, S.; Holst, J. J. No reactive hypoglycaemia in type 2 diabetic patients after subcutaneous administration of GLP-1 and intravenous glucose. Diabetic Med. 2001, 18(2), 144-149.
30. Wettergren, A.; Schjoldager, B.; Mortensen, P. E.; Myhre, J.; Christiansen, J.; Holst, J. J. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig. Dis. Sci. 1993, 38(4), 665-673.
31. Flint, A.; Raben, A.; Astrup, A.; Holst, J. J. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J. Clin. Invest. 1998, 101(3), 515-520.
32. Drucker, D. J.; Philippe, J.; Mojsov, S.; Chick, W. L.; Habener, J. F. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc. Natl. Acad. Sci. U.S.A. 1987, 84(10), 3434-3438.
33. Bulotta, A.; Hui, H.; Anastasi, E.; Bertolotto, C.; Boros, L. G.; Di Mario, U.; Perfetti, R. Cultured pancreatic ductal cells undergo cell cycle re-distribution and β-cell-like differentiation in response to glucagon-like peptide-1. J. Mol. Endocrinol. 2002, 29(3), 347-360.
34. Egan, J. M.; Bulotta, A.; Hui, H.; Perfetti, R. GLP-1 receptor agonists are growth and differentiation factors for pancreatic islet beta cells. Diabetes/Met. Res. Rev. 2003, 19(2), 115-123.
35. Stoffers, D. A.; Kieffer, T. J.; Hussain, M. A.; Drucker, D. J.; Bonner-Weir, S.; Habener, J. F.; Egan, J. M. Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 2000, 49(5), 741-748.
36. Oerskov, C.; Holst, J. J.; Nielsen, O. V. Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107)amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology 1988, 123(4), 2009-2013.
37. Umezawa, H.; Aoyagi, T.; Ogawa, K.; Naganawa, H.; Hamada, M.; Takeuchi, T. Diprotins A and B, inhibitors of dipeptidyl aminopeptidase IV, produced by bacteria. J. Antibiot. 1984, 37 (4), 422-425.
38. Rahfeld, J.; Schierhorn, M.; Hartrodt, B.; Neubert, K.; Heins, J. Are diprotin A (ile-pro-ile) and diprotin B (val-pro-leu) inhibitors or substrates of dipeptidyl peptidase IV? Biochim. Biophys. Acta 1991, 1076, 314-316.
39. Hiramatsu, H.; Yamamoto, A.; Kyono, K.; Higashiyama, Y.; Fukushima, C.; Shima, H.; Sugiyama, S.; Inaka, K.; Shimizu, R. The crystal structure of human dipeptidyl peptidase IV (DPPIV) complex with diprotin A. Biol. Chem. 2004, 385, 561-564.
40. Thoma, R.; Loeffler, B.; Stihle, M.; Huber, W.; Ruf, A.; Hennig, M. Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV. Structure 2003, 11, 947-959.
41. Boduszek, B.; Oleksyszyn, J.; Kam, C.-M.; Selzler, J.; Smith, R. E.; Powers, J. C. Dipeptide phosphonates as inhibitors of dipeptidyl peptidase IV. J. Med. Chem. 1994, 37, 3969-3976.
42. Lambeir, A.-M.; Borloo, M.; De Meester, I.; Belyaev, A.; Augustyns, K.; Hendriks, D.; Scharpé, S.; Haemers, A. Dipeptide-derived diphenyl phosphonate esters: mechanism-based inhibitors of dipeptidyl peptidase IV. Biochim. Biophys. Acta 1996, 1290, 76-82.
43. Flentke, G. R.; Munoz, E.; Huber, B. T.; Plaut, A. G.; Kettner, C. A.; Bachovchin, W. W. 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.
44. Demuth, H.-U,; Neumann, U.; Barth, A. Reactions between dipeptidyl peptidase IV and diacyl hydroxylamines: mechanistic investigations. J. Enzyme Inhibit. 1989, 2 (4), 239-248.
45. Ferraris, D.; Ko, Y.-S.; Calvin, D.; Chiou, T.; Lautar, S.; Thomas, B.; Wozniak, K.; Rojas, C.; Kalish, V.; Balyakov; S. Ketopyrrolidines and ketoazetidines as potent dipeptidyl peptidase IV (DPP-IV) inhibitors. Bioorg. Med, Chem. Lett. 2004, 14, 5579-5583.
46. Ashworth, D. M.; Atrash, B.; Baker, G. R.; Baxter, A. J.; Jenkins, P. D.; Jones, D. M.; Szelke, M. 2-Cyanopyrrolidides as potent, stable inhibitors of dipeptidyl peptidase IV. Bioorg. Med. Chem. Lett. 1996, 6(10), 1163- 1166.
47. Ashworth, D. M.; Atrash, B.; Baker, G. R.; Baxter, A. J.; Jenkins, P. D.; Jones, D. M.; Szelke, M. 4-Cyanothiazolidides as very potent, stable inhibitors of dipeptidyl peptidase IV. Bioorg. Med. Chem. Lett. 1996, 6(22), 2745-2748.
48. Villhauer, E. B. Preparation of N-aminoacetyl-2-cyanopyrrolidines as dipeptidylpeptidase IV inhibitors. PCT Int. Appl. WO 9819998 A2, 1998.
49. Villhauer, E. B. Preparation of N-glycyl-2-cyanopyrrolidines as DPP-IV inhibitors. PCT Int. Appl. WO 2000034241 A1, 2000.
50. Robl, J. A.; Sulsky, R. B.; Augeri, D. J.; Magnin, D. R.; Hamann, L. G.; Betebenner, D. A. Preparation of fused cyclopropylpyrrolidine-based inhibitors of dipeptidyl peptidase IV. PCT Int. Appl. WO 2001068603 A2, 2001.
51. Augustyns, K. J. L.; Lambeir, A. M.; Borloo, M.; De Meester, I.; Vedernikova, I.; Vanhoof, G.; Hendriks, D.; Scharpe, S.; Haemers, A. Pyrrolidides: synthesis and structure-activity relationship as inhibitors of dipeptidyl peptidase IV. Eur. J. Med. Chem. 1997, 32(4), 301-309.
52. Fukushima, H.; Hiratate, A.; Takahashi, M.; Saito, M.; Munetomo, E.; Kitano, K.; Saito, H.; Takaoka, Y; Yamamoto, K. Synthesis and structure-activity relationships of potent 3- or 4-substituted-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem 2004, 12, 6053-6061.
53. Fukushima, H.; Takahashi, M.; Mikami, A. Preparation of cyanofluoropyrrolidine derivatives as dipeptidyl peptidase IV inhibitors. PCT Int. Appl. WO 2004101514 A1, 2004.
54. Ahn, J.; Kim, H.-M.; Jung, S. H.; Kang, S. K.; Kim, K. R.; Rhee, S. D.; Yang, S.-D.; Cheon, H. G.; Kim, S. S. Synthesis and DP-IV inhibition of cyano-pyrazoline derivatives as potent anti-diabetic agents. Bioorg. Med. Chem. Lett. 2004, 14, 4461-4465.
55. Sulsky, R. B.; Robl, J. A. Preparation of 2,1-oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV. PCT Int. Appl. WO 2002083128 A1, 2002.
56. Villhauer, E. B.; Brinkmann, J. A.; Naderi, G. B.; Burkey, B. F.; Dunning, B. E.; Prasad, K.; Mangold, B. L., Russell, M. E.; Hughes, T. E. 1- 3-Hydroxy-1-adamantyl]amino]acetyl]-2-cyano-(S)-pyrrolidine: a pot ent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem, 2003, 46(13), 2774-2789.
57. Damon, R. Tetrahydroisoquinoline 3-carboxamide derivatives. US Pat. Appl. US 6,172,081 B1, 2001.
58. Wagner, H.; Schoenafinger, K.; Jaehne, G.; Gaul, H.; Buning, C.; Tschank, G.; Werner, U. Preparation of 6-amino-3-cyano-5-oxohexahydropyrrolo[2,1-b]thiazoles as dipeptidyl peptidase IV (DPP-IV) inhibitors. PCT Int. Appl. WO 2005012312 A1, 2005.
59. Engel, M.; Hoffmann, T.; Wagner, L.; Wermann, M.; Heiser, U.; Kiefersauer, R.; Huber, R.; Bode, W.; Demuth, H. U.; Brandstetter, H. The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism. Proc. Natl. Acad. Sci. USA 2003, 100(9), 5063-5068.
60. Hughes, T. E.; Mone, M. D.; Russell, M. E.; Weldon, S. C.; Villhauer, E. B. 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, 28, 11597-11603.
61. Takasaki, K.; Iwase, M.; Nakajima, U.; Nomoto, Y.; Nakanishi, S.; Higo, K. K579, a slow binding inhibitor of dipeptidyl peptidase IV, is a long-acting hypoglycemic agent. Eur. J. Pharmacol. 2004, 486, 335-342.
62. Boehringer, M.; Hunziker, D.; Kuehne, H.; Loeffler, B. M.; Sarabu, R.; Wessel, H.-P. Preparation of N-aminoacetyl-substituted pyrrolidines as dipeptidyl peptidase IV inhibitors. PCT Int. Appl. WO 2003037327 A1, 2003.
63. Magnin, D. R.; Robl, J. A.; Sulsky, R. B.; Augeri, D. J.; Huang, Y.; Simpkins, L. M.; Taunk, P. C.; Betebenner, D. A.; Robertson, J. G.; Abboa-Offei, B. E.; Wang, A.; Cap, M.; Xin, L.; Tao, L.; Sitkoff, D. F.; Malley, M. F.; Gougoutas, J. Z.; Khanna, A.; Huang, Q.; Han, S.-P.; Parker, R. A.; Hamann, L. G. 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-L-cis-4,5-methanoprolinenitrile-based inhibitors. J. Med. Chem. 2004, 47(10), 2587-2598.
64. Evans, D. M. Preparation of 1-(2′-aminoacyl)-2-cyanopyrrolidine derivatives as novel antidiabetic agents. PCT Int. Appl. WO 2001040180 A2, 2001.
65. Neubert, K.; Born, I.; Faust, J.; Heins, J.; Barth, A.; Demuth, H.-U.; Rahfeld, J. U.; Steinmetzer, T. Preparation of amino acid amides as dipeptidyl peptidase IV inhibitors. Ger. (East) Pat. Appl. DD 296075 A5, 1991.
66. Parker, J. C.; Hulin, B.; Van Volkenburg, M. A.; Lopaze, M. G.; Sagawa, K.; O'Gorman, M. T.; Gerdin, K.; Andrews, K. M.; Brees, D. J.; Reagan W. J. A novel fluorinated cyclic amide inhibitor of dipeptidyl peptidase IV improves glucose tolerance in murine models of diabetes mellitus. American Diabetes Association, 63th annual scientific sessions 2003, New Orleans, Abstract No. 16-LB.
67. Parker, J. C.; Hulin, B. New fluorinated lysine derivatives are dipeptidyl peptidase-IV inhibitors - useful for the treatment of e.g. diabetes, hyperglycemia, arthritis, obesity and hyperlipidemia. US Pat. Appl. US2005043292 A1, 2005.
68. Caldwell, C. G.; Chen, P.; He, J.; Parmee, E. R.; Leiting, B.; Marsilio, F.; Patel, R. A.; Wu, J. K.; Eiermann, G. J.; Petrov, A.; He, H.; Lyons, K. A.; Thornberry, N. A.; Weber, A. E. Fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors. Bioorg, Med. Chem. Lett. 2004, 14, 1265-1268.
69. Hulin, B. Dipeptidyl peptidase IV inhibiting fluorinated cyclic amides. PCT Int. Appl. WO 2004046106 A1, 2004.
70. Rasmussen, H. B.; Branner, S.; Wiberg, F. C.; Wagtmann, N. Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat. Struct. Biol. 2003, 10, 19-25.
71. Parmee, E. R.; He, J.; Mastracchio, A.; Edmondson, S. D.; Colwell, L.; Eiermann, G.; Feeney, W. P.; Habulihaz, B.; He, H.; Kilburn, R.; Leiting, B.; Lyons, K.; Marsilio, F.; Patel, R. A.; Petrov, A.; Di Salvo, J.; Wu, J. K.; Thornberry, N. A.; Weber, A. E. 4-Amino cyclohexylglycine analogues as potent dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2004, 14(1), 43-46.
72. Mastracchio, A.; Parmee, E. R.; Leiting, B.; Marsilio, F.; Patel, R.; Thornberry, N. A.; Weber, A. E.; Edmondson, S. D. Heterocycle fused cyclohexylglycine derivatives as novel dipeptidyl peptidase-IV inhibitors. Heterocycles 2004, 62, 203-206.
73. Weber, A. E. Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. J. Med. Chem. 2004, 47(17), 4135-4141.
74. Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He, H.; Hickey, G. J.; Kowalchick, J. E.; Leiting, B.; Lyons, K.; Marsilio, F.; McCann, M. E.; Patel, R. A.; Petrov, A.; Scapin, G.; Patel, S. B.; Roy, R. S.; Wu, J. K.; Wyvratt, M. J.; Zhang, B. B.; Zhu, L.; Thornberry, N. A.; Weber, A. E. (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(1), 141-151.
75. Wiedemann, P. E.; Trevillyan, J. M. Dipeptidyl peptidase IV inhibitors for the treatment of impaired glucose tolerance and type 2 diabetes. Curr. Opin. Investig. Drugs 2003, 4(4), 412-420.
76. Himmelsbach, F.; Mark, M. Preparation of xanthines as dipeptidyl peptidase IV (DPP-IV) inhibitors. Ger. Pat. Appl. DE10109021, 2002.
77. Himmelsbach, F.; Mark, M.; Eckhardt, M.; Langkopf, E.; Maier, R.; Lotz, R. Preparation of xanthine derivatives as dipeptidyl peptidase-IV inhibitors. PCT. Int. Appl. WO2002068420, 2002.
78. Kanstrup, A. B.; Christiansen, L. B.; Lundbeck, J. M.; Sams, C. K.; Kristiansen, M. Preparation of piperazinylpurinediones as inhibitors of dipeptidylpeptidase IV. PCT. Int. Appl. WO2002002560, 2002.
79. Himmelsbach, F.; Langkopf, E.; Eckhardt, M.; Maier, R.; Mark, M.; Tadayyon, M.; Lotz, R. Preparation of xanthines as inhibitors of dipeptidyl peptidase IV (DPP-IV). Ger. Pat. Appl. DE10251927, 2004.
80. Yoshikawa, S.; Emori, E.; Matsuura, F.; Clark, R.; Ikuta, H.; Yasuda, N.; Nagakura, T.; Yamazaki, K.; Aoki, M. Preparation of xanthine derivatives as DPP-IV inhibitors. Eur. Pat. Appl. EP1338595, 2003.
81. Kanstrup, A. B.; Sams, C. K.; Lundbeck, J. M.; Christiansen, L. B.; Bowler, A. N. Preparation of purine derivatives as inhibitors of the enzyme DPP-IV. PCT. Int. Appl. WO2003024965, 2003.
82. Kanstrup, A. B.; Sams, C. K.; Lundbeck, J. M.; Christiansen, L. B.; Kristiansen, M. Preparation of dipeptidyl peptidase IV (DPP-IV) inhibiting purine derivatives for the treatment of diabetes. PCT. Int. Appl. WO2003004496, 2003.
83. Yasuda, N.; Yamazaki, K. Preparation of piperazine derivatives as dipeptidyl peptidase IV inhibitors. PCT. Int. Appl. WO2004028524, 2004.
84. Nakahira, H.; Hochigai, H. Preparation of xanthine derivatives as dipeptidyl peptidase IV inhibitors for the treatment of diabetes. PCT. Int. Appl. WO2004048379, 2004.
85. Eckhardt, M.; Himmelsbach, F.; Langkopf, E.; Maier, R.; Mark, M.; Tadayyon, M. Preparation of xanthine derivatives as dipeptidyl peptidase IV inhibitors. Ger. Pat. Appl. DE10254304, 2004.
86. Himmelsbach, F.; Langkopf, E.; Eckhardt, M.; Mark, M.; Maier, R.; Lotz, R. R. H.; Tadayyon, M. Preparation of 8-[3-aminopiperidin-1-yl]xanthines as dipeptidyl peptidase-IV (DPP-IV) inhibitors. PCT. Int. Appl. WO2004018468, 2004.
87. Eckhardt, M.; Himmelsbach, F.; Langkopf, E.; Maier, R.; Mark, M.; Lotz, R. Preparation of xanthines as dipeptidylpeptidase IV inhibitors for the treatment of diabetes. Ger. Pat. Appl. DE1023 8470, 2004.
88. Kanstrup, A.; Bjelke, J. R.; Bowler, A. N.; Branner, S.; Carr, R. D.; Christensen, I. T.; Christiansen, L. B.; Daugaard, J. R.; Kilburn, J. P.; Kristiansen, M.; Lundbeck, J. M.; Rasmussen, H. B.; Rolin, B.; Sams, C. G. Design, synthesis, and biological evaluation of a series of potent xanthine-based inhibitors of the enzyme DPP-IV. Poster presentation at the 6th Winter Conference of the Medicinal and Bioorganic Chemistry Foundation, Steamboat Springs, Colorado, U.S.A., 2005.
89. Eckhardt, M.; Hauel, N.; Langkopf, E.; Himmelsbach, F.; Kauffmann-Hefner, I.; Tadayyon, M.; Mark, M. Preparation of imidazopyridazinones and related compounds as dipeptidyl peptidase IV (DPP-IV) inhibitors for the treatment of diabetes. PCT. Int. Appl. WO2004111051, 2004.
90. Feng, J.; Gwaltney, S. L.; Kaldor, S. W.; Stafford, J. A.; Wallace, M. B.; Zhang, Z. Dipeptidyl peptidase inhibitors. PCT. Int. Appl. WO2004087053, 2004.
91. Edmondson, S. D.; Mastracchio, A.; Beconi, M.; Colwell, L. F.; Habulihaz, B.; He, H.; Kumar, S.; Leiting, B.; Lyons, K. A.; Mao, A.; Marsilio, F.; Patel, R. A.; Wu, J. K.; Zhu, L.; Thornberry, N. A.; Weber, A. E.; Parmee, E. R. Potent and selective proline derived dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2004, 14(20), 5151-5155.
92. Edmondson, S. D.; Parmee, E.; Weber, A. E.; Xu, J. Preparation of peptides as dipeptidyl peptidase inhibitors for the treatment of diabetes. PCT Int. Appl. WO 2003000180 A2, 2003.
93. Brockunier, L. L.; He, J.; Colwell, L. F.; Habulihaz, B.; He, H.; Leiting, B.; Lyons, K. A.; Marsilio, F.; Patel, R. A.; Teffera, Y.; Wu, J. K.; Thornberry, N. A.; Weber, A. E.; Parmee, E. R. Substituted piperazines as novel dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2004, 14(18), 4763-4766.
94. Duffy, J. L.; Edmondson, S. D.; Kim, D.; Kirk, B. A.; Wang, L.; Weber, A. E. Preparation of 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes. PCT Int. Appl. WO 2004058266 A1 2004.
95. Kim, D.; Kowalchick, J. E. Preparation of aminoacyl triazolopyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes. PCT Int. Appl. WO 2004032836 A2, 2004.
96. Brockunier, L. L.; Duffy, J. L.; Kim, D.; Parmee, E. R.; Weber, A. E. Preparation of aminoacylimidazo- and triazolopyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes. PCT Int. Appl. WO 2003082817 A2, 2003.
97. Edmondson, S. D.; Fisher, M. H.; Kim, D.; MacCoss, M.; Parmee, E. R.; Weber, A. E.; Xu, J. Preparation of β-amino tetrahydroimidazo[1,2-a]pyrazines and tetrahydrotrioazolo[4,3-a]pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes. PCT Int. Appl. WO 2003004498 A1, 2003.
98. Biftu, T.; Liang, G.-B.; Feng, D. D.; Weber, A. E. Preparation of hexahydrodiazepinones as dipeptidyl peptidase IV inhibitors. PCT Int. Appl. WO2005011581 A2, 2005.
99. Coppola, G. M.; Zhang, Y. L.; Schuster, H. F.; Russell, M. E.; Hughes, T. E. 1-Aminomethylisoquinoline-4-carboxylates as novel dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2000, 10, 1555-1558.
100. Oi, S.; Ikedou, K.; Takeuchi, K.; Ogino, M.; Banno, Y.; Tawada, H.; Yamane, T. Preparation of isoquinolinones as dipeptidyl peptidase IV inhibitors for the prophylaxis or treatment of diabetes. PCT. Int. Appl. WO2002062764, 2002.
101. Oi, S.; Maezaki, H.; Ikedou, K. Preparation of fused heterocyclic compounds as peptidase inhibitors. PCT. Int. Appl. WO2004014860, 2004.
102. Boehringer, M.; Loeffler, B.-M.; Peters, J.-U.; Steger, M.; Weiss, P. Preparation of novel pyridin- and pyrimidin-derivatives as DPP-IV inhibitors. PCT. Int. Appl. WO2003068757, 2003.
103. Boehringer, M.; Loeffler, B. M.; Peters, J.-U.; Riemer, C.; Weiss P. Preparation of novel pyridine- and quinoline-derivatives as DPP-IV inhibitors. PCT. Int. Appl. WO2003068748, 2003.
104. 5 fold activity increase by optimization of aromatic substituents. Bioorg. Med. Chem. Lett. 2004, 14(6), 1491-1493.
105. Peters, J.-U.; Weber, S.; Kritter, S.; Weiss, P.; Wallier, A.; Zimmerli, D.; Boehringer, M.; Steger, M.; Loeffler, B.-M. Aminomethylpyridines as DPP-IV inhibitors. Bioorg. Med. Chem. Lett. 2004, 14(13), 3579-3580.
106. Peters, J.-U.; Hunziker, D.; Fischer, H.; Kansy, M.; Weber, S.; Kritter, S.; Müller, A.; Wallier, A.; Ricklin, F.; Boehringer, M.; Poli, S. M.; Csato, M.; Loeffler, B.-M. An aminomethylpyrimidine DPP-IV inhibitor with improved properties. Bioorg. Med. Chem. Lett. 2004, 14(13), 3575-3578.
107. Boehringer, M.; Kuhn, B.; Mattei, P.; Narquizian, R. Preparation of pyrido[2,1-a]isoquinoline derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors. US Pat. Appl. US2004259903, 2004.
108. Boehringer, M.; Kuhn, B.; Luebbers, T.; Mattei, P.; Narquizian, R.; Wessel, H. P. Preparation of pyrido[2,1-a]isoquinoline derivatives as potent dipeptidyl peptidase IV (DPP-IV) inhibitors. US Pat. Appl. US2004259902, 2004.
109. Gobbi, L. C.; Luebbers, T.; Mattei, P.; Narquizian, R.; Wyss, P. C. Preparation of pyrido[2,1-a]isoquinoline derivatives as DPP-IV inhibitors. PCT. Int. Appl. WO2003055881, 2003.
110. Yasuda, N.; Nagakura, T.; Yamazaki, K.; Yoshikawa, S.; Okada, T.; Ikuta, H.; Koyanagi, M. Preparation of N-carbamoylazoles as dipeptidyl peptidase IV inhibitors. Eur. Pat. Appl. EP1258480, 2002.
111. Cheon, H.-G.; Lee, C.-M.; Kim, B.-T.; Hwang, K.-J. Lead discovery of quinoxalinediones as an inhibitor of dipeptidyl peptidase-IV (DPP-IV) by high-throughput screening. Bioorg. Med. Chem. Lett. 2004, 14(10), 2661-2664.
112. Akiyama, T.; Abe, M.; Harada, S.; Kojima, F.; Sawa, R.; Takahashi, Y.; Naganawa, H.; Homma, Y.; Hamada, M.; Yamaguchi, A.; Aoyagi, T.; Muraoka, Y.; Takeuchi, T. Sulphostin, a potent inhibitor for dipeptidyl peptidase IV from Streptomyces sp. MK251-43F3. J. Antibiot. 2001, 54(9), 744-746.
113. Abe, M.; Akiyama, T.; Umezawa, Y.; Yamamoto, K.; Nagai, M.; Yamazaki, H.; Ichikawa, Y.-I.; Muraoka, Y. Synthesis and biological activity of sulphostin analogues, novel dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. 2005, 13(3), 785-797.
114. Sorbera, L. A.; Revel, L.; Castaner, J. P32/98: Antidiabetic dipeptidyl peptidase IV inhibitor. Drugs of the Future 2001, 26, 859-864.
115. Demuth, H.-U.; Glund, K.; Banke-Bochita, J.; Rost, K.-L.; Fischer, S.; Hanefeld, M.; McIntosh, C.; Pederson, R. A. Dipeptidyl peptidase IV (DP IV)-modulations as treatment of impaired glucose tolerance and NIDDM. Regul. Pept. 2000, 94(1-3), 16.
116. Demuth, H.-U.; Hoffman, T.; Glund, K.; McIntosh, C.; Pederson, R. A.; Fuecker, K.; Fischer, S.; Hanefeld, M. Single dose treatment of type 2 diabetics by the DP IV-inhibitor P32/98. Diabetes Res. Clin. Pract. 2000, 50(Suppl. 1), 386.
117. Ahren, B.; Simonsson, E.; Larsson, H.; Landin-Olsson, M.; Torgeirsson, H.; Jansson, P.-A.; Sandqvist, M.; Bavenholm, P.; Efendic, S.; Eriksson, J. W.; Dickinson, S.; Holmes, D. Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes. Diabetes Care 2002, 25(5), 869-875.
118. Ahren, B.; Landin-Olsson, M.; Svensson, M.; Holmes, D.; Schweizer. A.; Inhibition of dipeptidyl peptidase-IV reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J. Clin. Endocrionol. Metabol. 2004, 89(5), 2078-2084.
119. Pratley, R.; Galbreath, E. Twelve-week monotherapy with the DPP-4 inhibitor LAF237 improves glycemic control in patients with type 2 diabetes (T2DM). American Diabetes Association, 64th Annual Scientific Sessions 2004, Orlando Florida, Abstract 355-OR.
120. Ahren, B.; Gomis, R.; Standl, E.; Mills, D.; Schweizer, A. Twelve-and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 2004, 27(12), 2874-2880.
121. Herman, G. A.; Zhao, P.-L.; Dietrich, B.; Golor, G.; Schrodter, A.; Keymeulen, B.; Lasseter, K. C.; Kipnes, M. S.; Hilliard, D.; Tanen, M.; De Lepeleire, I.; Cilissen, C.; Stevens, C.; Tanaka, W.; Gottesdiener, K. M.; Wagner, J. A. The DP-IV inhibitor MK-0431 enhances active GLP-1 and reduces glucose following an OGTT in type 2 diabetics. American Diabetes Association, 64th Annual Scientific Sessions 2004, Orlando, Florida, Abstract 353-OR.
122. Brazg, R.; Thomas, K.; Zhao, P.; Xu, L.; Chen, X.; Stein, P. Effect of adding MK-0431 to on-going metformin therapy in type 2 diabetic patients who have inadequate glycemic control on metformin. American Diabetes Association, 65th Annual Scientific Sessions 2005, San Diego, California, Abstract 11-OR.
123. Scott, R.; Herman, G.; Zhao, P.; Chen, X.; Wu, M.; Stein, P. Twelve-week efficacy study and tolerability of MK-0431, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in the treatment of type 2 diabetes. American Diabetes Association, 65th Annual Scientific Sessions 2005, San Diego, California, Abstract 41-OR.
124. Stevens, C.; Van Dyck, K.; Yi, B.; Bergman, A.; De Smet, M.; Snyder, K.; Hilliard, D.; Tanaka, W.; Wang, A.; Zeng, W.; Musson, D.; Winchell, G.; Ramael, S.; Gottesdiener, K.; Wagner, J.; Herman, G. Single doses of MK-0431, an inhibitor of dipeptidyl-peptidase-IV, raise active GLP-1 levels without causing hypoglycemia in healthy subjects. American Diabetes Association, 65th Annual Scientific Sessions 2005, San Diego, California, Abstract 493-P.
125. Herman, G. A.; Bergman, A.; Liu, F.; Stevens, C.; Wang, A. Q.; Zeng, W.; Chen, L.; Snyder, K.; Hilliard, D.; Tanaka, W.; Davies, M.; Lasseter, K. C.; Blum, R.; Wagner, J. A. Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple doses of MK-0431 over 28 days in middle-aged, obese subjects. American Diabetes Association, 65th Annual Scientific Sessions 2005, San Diego, California, Abstract 497-P.
126. Herman, G.; Hanefeld, M.; Wu, M.; Chen, X.; Zhao, P.; Stein, P. Effect of MK-0431, a dipeptidyl-peptidase IV (DPP-IV) inhibitor, on glycemic control after 12 weeks in patients with type 2 diabetes. American Diabetes Association, 65th Annual Scientific Sessions 2005, San Diego, California, Abstract 541-P.
127. Data presented by Bristol-Myers Squibb at their November 2004 investor meeting.
128. Duttaroy, A.; Voelker, F.; Merriam, K.; Zhang, X.; Ren, X.; Burkey, B. The DPP-4 inhibitor vildagliptin increases pancreatic beta cell neogenesis and decreases apoptosis. American Diabetes Association, 65th Annual Scientific Sessions 2005, San Diego, California, Abstract 572-P.
129. Gerber, P. R. Peptide mechanics: A force field for peptides and proteins working with entire residues as smallest units. Biopolymers 1992, 32, 1003-1017.