Discovery and preclinical profile of saxagliptin (BMS-477118): A highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

Journal of Medicinal Chemistry

Volumn 48, Issue 15, 2005, Pages 5025-5037

  Augeri, David J ^a,b   Robl, Jeffrey A ^a   Betebenner, David A ^a,c   Magnin, David R ^a   Khanna, Ashish ^a   Robertson, James G ^a   Wang, Aiying ^a   Simpkins, Ligaya M ^a   Taunk, Prakash ^a   Huang, Qi ^a   Han, Song Ping ^a   Abboa Offei, Benoni ^a   Cap, Michael ^a   Xin, Li ^a   Tao, Li ^a   Tozzo, Effie ^a   Welzel, Gustav E ^a   Egan, Donald M ^a   Marcinkeviciene, Jovita ^a   Chang, Shu Y ^a   Biller, Scott A ^a,d   Kirby, Mark S ^a   Parker, Rex A ^a   Hamann, Lawrence G ^a   more..

^a BRISTOL MYERS SQUIBB   (United States)

^b LEXICON PHARMACEUTICALS INC   (United States)

^c ABBOTT LABORATORIES   (United States)

^d NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALKYL GROUP; AMANTADINE DERIVATIVE; ANTIDIABETIC AGENT; DIPEPTIDYL PEPTIDASE IV; DIPEPTIDYL PEPTIDASE IV INHIBITOR; DRUG METABOLITE; GLUCOSE; GLYCINE DERIVATIVE; INSULIN; PROLINE DERIVATIVE; SAXAGLIPTIN; UNCLASSIFIED DRUG; VINYL DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG POTENCY; ENZYME INHIBITION; GLUCOSE BLOOD LEVEL; HUMAN; INSULIN RELEASE; MALE; MODEL; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; ORAL GLUCOSE TOLERANCE TEST; OXYGENATION; RAT; STRUCTURE ACTIVITY RELATION;

ADAMANTANE; ANIMALS; ANTIGENS, CD26; BIOLOGICAL AVAILABILITY; BLOOD GLUCOSE; DIABETES MELLITUS, TYPE 2; DIPEPTIDES; GLUCOSE TOLERANCE TEST; GLYCINE; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; MALE; MICE; MICE, OBESE; MICROSOMES, LIVER; NITRILES; PROLINE; PROTEASE INHIBITORS; RATS; RATS, ZUCKER; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 22744449063     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm050261p     Document Type: Article

References (66)

1. Ford, E. S.; Giles, W. H.; Dietz, W. H. Prevalence of the metabolic syndrome among US adults. J. Am. Med. Assoc. 2002, 287, 356-359.
2. (a) Ross, S. A.; Gulve, E. A.; Wang, M. Chemistry and biochemistry of type 2 diabetes. Chem. Rev. 2004, 104, 1255-1282.
3. (b) Skyler, J. S. Diabetes mellitus: Pathogenesis and treatment strategies. J. Med. Chem. 2004, 47, 4113-4117.
4. (a) Knudsen, L. B. Glucagon-like Peptide-1: The basis of anew class of treatment for type 2 diabetes. J. Med. Chem. 2004, 47, 4128-4134.
5. (b) Weber, A. E. Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. J. Med. Chem. 2004, 47, 4135-4141.
6. (a) MacDonald, P. E.; El-kholy, W.; Riedel, M. J.; Salapatek, A. M. P.; Light, P. E.; Wheeler, M. B. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 2002, 51 (Suppl. 3), S434-S442.
7. (b) Drucker, D. J. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003, 26, 2929-2940.
8. (a) Stoffers, D.; Kieffer, T.; Hussain, M. A.; Drucker, D. J.; Bonner-Weir, S.; Habener, J.; Egan, J. Insulinotropic GLP-1 peptide agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 2000, 49, 741-748.
9. (b) Reimer, M. K.; Holst, J. J.; Ahrén, B. Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice. Eur. J. Endocrinol. 2002, 146, 717-727.
10. (c) Pospisilik, J. A.; Stafford, S. G.; Demuth, H.-U.; Brownsey, R.; Parkhouse, W.; Finegood, D. T.; McIntosh, C. H. S.; Pederson, R. A. 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.
11. (d) Buteau, J.; Foisy, S.; JoIy, E.; Prentki, M. Glucagon-like peptide-1 induces pancreatic β-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes 2003, 52, 124-132.
12. (e) Pospisilik, J. A.; Martin, J.; Doty, T.; Ehses, J. A.; Pamir, N.; Lynn, F. C.; Piteau, S.; Demuth, H.-U.; McIntosh, C. H. S.; Pederson, R. A. Dipeptidyl peptidase IV inhibitor treatment stimulates β-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes 2003, 52, 741-750.
13. (f) Drucker, D. J. Glucagon-like peptide-1 and the islet β-cell: Augmentation of cell proliferation and inhibition of apoptosis. Endocrinology 2003, 144, 5145-5148.
14. (a) Wettergren, A.; Wojdemann, M.; Holst, J. J. The inhibitory effect of glucagon-like peptide-1 (7-36)amide on antral motility is antagonized by its N-terminally truncated primary metabolite GLP-1 (9-36)amide. Peptides 1998, 19(5), 877-882.
15. (b) Knudsen, L. B.; Pridal, L. Glucagon-like peptide-1-(9-36)amide is a major metabolite of glucagon-like peptide-1-(7-36)amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor. Eur. J. Pharmacol. 1996, 318 (2-3), 429-435.
16. (a) Kieffer, T. J.; McIntosh, C. H. S.; Peterson, R. A. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide-1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 1995, 136, 3585-3596.
17. 2-terminus in type 2 diabetics and in healthy subjects. Diabetes 1995, 44, 1126-1131.
18. (c) Mentlein, R. Dipeptidyl peptidase-IV (CD26)-Role in the inactivation of regulatory peptides. Regul. Peptides 1999, 85, 9-24.
19. (d) Hansen, L.; Deacon, C. F.; Orskov, C.; Holst, J. J. GLP-1(7-36)amide is transformed to GLP-1(9-36)amide by DPP-IV in the capillaries supplying the L-cells of the porcine intestine. Endocrinology 1999, 140, 5356-5363.
20. Vilsbøll, T.; Krarup, T.; Madsbad, S.; Holst, J. J. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul. Peptides 2003, 114, 115-121.
21. 2-terminal signal sequence as the membrane-anchoring domain. J. Biol. Chem. 1989, 264, 3596-3601.
22. (a) Rasmussen, H. B.; Branner, S.; Wiberg, F. C.; Wagtmann, N. Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nature Struct. Biol. 2003, 10, 19-25.
23. (b) Hiramatsu, H.; Kyono, K.; Shima, H.; Fukushima, C.; Sugiyama, S.; Inaka, K.; Yamamoto A.; Shimizu, R. Crystallization and preliminary X-ray study of human dipeptidyl peptidase IV (DPPIV). Acta Crystallogr. 2003, D59, 595-596.
24. (c) Hiramatsu, H.; Kyono, K.; Higashiyama, Y.; Fukushima, C.; Shima, H.; Sugiyama, S.; Inaka, K.; Yamamoto A.; Shimizu, R. The structure and function of human dipeptidyl peptidase-IV, possessing a unique eight-bladed β-propeller fold. Biochem. Biophys. Res. Commun. 2003, 302, 849-854.
25. (d) Engel, M.; Torsten, H.; 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. U.SA. 2003, 100, 5063-5068.
26. (e) Thorma, R.; Löffler, 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.
27. (f) Ajami, K.; Abbott, C. A.; Obradovic, M.; Gysbers, V.; Kähne, T.; McCaughan, G. W.; Gorrell, M. D. Structural requirements for catalysis, expression, and dimerization in the CD26/DPIV gene family. Biochemistry 2003, 42, 694-701.
28. (a) Ahrén, 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, 869-875.
29. (b) Ahrén, B.; Landin-Olsson, M.; Jansson, P.-A.; Eriksson, J.; Pacini, G.; Thomaseth, K.; Schweizer, A. The DPPIV inhibitor, LAF237, reduces fasting and postprandial glucose in subjects with type 2 diabetes over a 4 week period by increasing active GLP-1, sustaining insulin and reducing glucagon. Diabetes 2003, 52 (S1), A15.
30. (c) Ahrén, 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, 2874-2880.
31. (a) 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. Exp. Opin. Ther. Pat. 2003, 13, 499-510.
32. (b) 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, 412-420.
33. (a) 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-Aminocyclohexylglycine analogues as potent dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 43-46.
34. (b) Ashton, W. T.; Dong, H.; Sisco, R. M.; Doss, G. A.; Leiting, B.; Patel, R. A.; Wu, J. K.; Marsilio, F.; Thornberry, N. A.; Weber, A. E. 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.
35. (c) 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.
36. (d) Brockunier, L. L.; He, J.; Colwell, L. F., Jr.; 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, 4763-4766.
37. (e) Edmondson, S. D.; Mastracchio, A.; Beconi, M.; Colwell, L. F., Jr.; 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, 5151-5155.
38. (f) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G.; J.; Fisher, M. H.; He, H.; Hickey, G. J.; Kowalchik, J. E.; Leiting, B.; Lyons, K. A.; 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, 141-151.
39. 5-fold activity increase by optimization of aromatic substituents. Bioorg. Med. Chem. Lett. 2004, 14, 1491-1493.
40. (b) Peters, J.-U.; Hunziker, D.; Fischer, H.; Kansay, M.; Weber, S.; Kritter, S.; Müller, A.; Wallier, Á.; 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, 3575-3578.
41. (c) Peters, J.-U.; Weber, S.; Kritter, S.; Weiss, P.; Wallier, A.; Zimmerli, D.; Boehringer, M.; Steger, M.; Loeffler, B.-M. Aminomethylpyrimidines as DPP-IV Inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 3579-3580.
42. (a) Sorbera, L. A.; Revel, L.; Castaner, J. P32/98: Antidiabetic dipeptidyl-peptidase IV inhibitor. Drugs Future 2001, 26, 859-864.
43. (b) Pauly, R. P.; Demuth, H.-U.; Rosche, F.; Schmidt, J.; White, H. A.; Lynn, F.; McIntosh, C. H. S.; Pederson, R. A. Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor Ile-thiazolidide. Metab., Clin. Exp. 1999, 48, 385-389.
44. (c) Pederson, R. A.; White, H. A.; Schlenzig, D.; Pauly, R. P.; McIntosh, C. H. S.; Demuth, H.-U. Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide. Diabetes 1998, 47, 1253-1258.
45. 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. Biorg. Med. Chem Lett. 1996, 6, 1163-1166.
46. (a) 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, 38, 11597-11603.
47. (b) Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.; Dunning, B. E.; Mangold, B. L.; Mone, M. D., Russell, M. E.; Weldon, S. C.; Hughes, T. E. 1-[2-[(5-Cycanopyridine-2-yl)amino]-ethylamino]acetyl-2-(S)-pyrrolidine carbonitrile: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem. 2002, 45, 2362-2365.
48. (c) Villhauer, E. B.; Brinkman, 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)-pyrrolidide: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem. 2003, 46, 2774-2789.
49. Magnin, D. R.; Robl, J. A.; Sulsky, R. B.; Augeri, D. J.; Huang, Y.; Simpkins, L. M.; Taunk, P.; Betebenner, D. A.; Robertson, J. G.; Abboa-Offei, B.; Wang, A.; Cap, M.; Xing, 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 DPP-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, 2587-2598.
50. (a) Grayson, I. Water-soluble carbodiimide-An efficient coupling agent for synthesis. Specialty Chem. 2000, 20, 86-88.
51. (b) Benoiton, N. L.; Kuroda, K. Studies on racemization during couplings using a series of model tripeptides involving activated residues with unfunctionalized side chains. Int. J. Pept. Protein Res. 1981, 17, 197-204.
52. (c) Hoeg-Jensen, T.; Havsteen Jakobsen, M.; Holm, A. A new method for rapid solution synthesis of shorter peptides by use of (benzotriazolyloxy) tripyrrolidinophosphonium hexafluorophosphate (Py BOP). Tetrahedron Lett. 1991, 32, 6387-90.
53. (d) Frerot, E.; Coste, J.; Pantaloni, A.; Dufour, M. N.; Jouin, P. PyBOP® and PyBroP: Two reagents for the difficult coupling of the α,α-dialklyl amino acid, Aib. Tetrahedron 1991, 47, 259-70.
54. Campagna, F.; Carotti, A.; Casini, G. A convenient synthesis of nitriles from primary amides under mild conditions. Tetrahedron Lett. 1977, 18, 1813-1816.
55. In cases where racemic Boc amino acids were coupled to the enantiomerically pure 4,5-methanoproline nitriles, the latter eluting isomer on silica gel chromatography (10%-40% EtOAc-hexanes) provides the L,L-isomer. These were confirmed by monitoring the activity against DDP-IV inhibition.
56. Kazmaier, U. Application of the ester enolate claisen rearrangement in the synthesis of amino acids containing quaternary carbon centers. J. Org. Chem. 1996, 61, 3694-3699.
57. Inaba, T.; Kozono, I.; Fujita, M.; Ogura, K. An efficient and practical synthesis of L-α-amino acids using CR)-phenylglycinol as a chiral auxiliary. Bull. Chem. Soc. Jpn. 1992, 65, 2359-2365.
58. Anderson, G. L.; Burks, W. A.; Harruna, I. I. Novel synthesis of 3-fluoro-1-aminoadamantane and some of its derivatives. Synth. Commun. 1988, 18, 1967-1974.
59. An extensive analysis of slow-binding kinetic properties of the present series of compounds will be reported elsewhere in due course.
60. Truett, G.; Bahary, N.; Friedman, J. M.; Leibel, R. L. The Zucker rat obesity gene fatty (fa) maps to chromosome 5 and is a homologue of the mouse diabetes (db) gene. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 7806-7809.
61. (a) McIntosh, C. H. S.; Pederson, R. A. Noninsulin-dependent animal models of diabetes mellitus. in experimental models of diabetes. Edited by John H. McNeill, CRC Press LLC, 1999, 337-398.
62. (b) Balkan, B.; Kwansnik, L.; Miserendino, R.; Holst, J. J.; 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 (11), 1324-1331.
63. (a) Ahrén, B.; Holst, J. J.; Mårtensson, H.; Balkan, B. Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice. Eur. J. Pharmacol. 2000, 404, 239-245.
64. (b) Conarello, S. L.; Li, Z.; Ronan, J.; Roy, R. S.; Zhu, L.; Jiang, G.; Liu, F.; Woods, J.; Zycband, E.; Moller, D. E.; Thornberry, N. A.; Zhang, B. B. Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 6825-6830.
65. Crystallographic data (excluding structure factors) for the TFA salt of 26 have been deposited with the Cambridge Crystallographic Data Centre. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 IEZ, UK.; fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
66. Morrison, J. F.; Walsh, C. T. The behavior and significance of slow-binding enzyme inhibitors. Adv. Enzymol. Relat. Areas Mol. Biol. 1988, 61, 201-301.