Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV

Journal of Medicinal Chemistry

Volumn 54, Issue 2, 2011, Pages 510-524

  Zhang, Zhiyuan ^a   Wallace, Michael B ^a   Feng, Jun ^a   Stafford, Jeffrey A ^a   Skene, Robert J ^a   Shi, Lihong ^a   Lee, Bumsup ^a   Aertgeerts, Kathleen ^a   Jennings, Andy ^a   Xu, Rongda ^a   Kassel, Daniel B ^a   Kaldor, Stephen W ^a   Navre, Marc ^a   Webb, David R ^a   Gwaltney, Stephen L ^a  

^a Takeda San Diego Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [2 (3 AMINOPIPERIDIN 1 YL) 5 FLUORO 6 OXO 6H PYRIMIDIN 1 YLMETHYL]BENZONITRILE; 2 [6 (3 AMINOPIPERIDIN 1 YL) 3 METHYL 2,4 DIOXO 3,4 DIHYDRO 2H PYRIMIDIN 1 YLMETHYL] 4 FLUOROBENZONITRILE; 2 [6 (3 AMINOPIPERIDIN 1 YL) 3 METHYL 2,4 DIOXO 3,4 DIHYDRO 2H PYRIMIDIN 1 YLMETHYL]BENZONITRILE; DIPEPTIDYL PEPTIDASE IV; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLUCOSE; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DIABETES MELLITUS; DRUG DESIGN; DRUG SYNTHESIS; ENZYME ACTIVITY; GLUCOSE BLOOD LEVEL; NONHUMAN; SINGLE DRUG DOSE;

ANIMALS; BINDING SITES; BIOLOGICAL AVAILABILITY; CRYSTALLOGRAPHY, X-RAY; CYTOCHROME P-450 ENZYME SYSTEM; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DOGS; MACACA FASCICULARIS; MODELS, MOLECULAR; PYRIMIDINONES; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 78751651182     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm101016w     Document Type: Article

References (46)

1. www.idf.org.
2. Drucker, D. J.; Nauck, M. A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes Lancet 2006, 368, 1696-1705
3. Holst, J. J. Glucagon-like peptide-1, a gastrointestinal hormone with a pharmaceutical potential Curr. Med. Chem. 1999, 6, 1005-1017
4. Deacon, C. F.; Holst, J. J.; Carr, R. D. Glucagon-like peptide-1: a basis for new approaches to the management of diabetes Drugs Today 1999, 35, 159-170
5. Livingston, J. N.; Schoen, W. R. Glucagon and glucagon-like peptide-1 Annu. Rep. Med. Chem. 1999, 34, 189-198
6. Barnett, A. Exenatide Expert Opin. Pharmacother. 2007, 8, 2593-2608
7. Cvetkovic, R. S.; Plosker, G. L. Exenatide: a review of its use in patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a sulfonylurea) Drugs 2007, 67, 935-954
8. Drab, S. R. Clinical studies of liraglutide, a novel, once-daily human glucagon-like peptide-1 analog for improved management of type 2 diabetes mellitus Pharmacotherapy 2009, 29, 43S-54S
9. Croom, K. F.; McCormack, P. L. Liraglutide: a review of its use in type 2 diabetes mellitus Drugs 2009, 69, 1985-2004
10. Russell-Jones, D. Molecular, pharmacological and clinical aspects of liraglutide, a once-daily human GLP-1 analogue Mol. Cell. Endocrinol. 2009, 297, 137-140
11. Edmondson, S. D.; Kim, D. Selective Dipeptidyl Peptidase IV Inhibitors for the Treatment of Type 2 Diabetes: The Discovery of Januvia (Sitagliptin). Antitargets: Prediction and Prevention of Drug Side Effects; Vaz, R. J.; Klabunde, T., Eds.; Methods and Principles in Medicinal Chemistry, Vol. 38; Wiley-VCH: Weinheim, Germany, 2008; pp 401 - 422.
12. Zerilli, T.; Pyon, E. Y. Sitagliptin phosphate: a DPP-4 inhibitor for the treatment of type 2 diabetes mellitus Clin. Ther. 2007, 29, 2614-2634
13. Weber, A. E.; Thornberry, N. Case history: Januvia (sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes Annu. Rep. Med. Chem. 2007, 42, 95-109
14. Thornberry, N. A.; Weber, A. E. Discovery of Januvia (sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes Curr. Top. Med. Chem. 2007, 7, 557-568
15. Lyseng-Williamson, K. A. Sitagliptin Drugs 2007, 67, 587-597
16. Augeri, D. J.; Robl, J. A.; Betebenner, D. A.; Magnin, D. R.; Khanna, A.; Robertson, J. G.; Wang, A.; Simpkins, L. M.; Taunk, P.; Huang, Q.; Han, S.-P.; Abboa-Offei, B.; Cap, M.; Xin, L.; Tao, L.; Tozzo, E.; Welzel, G. E.; Egan, D. M.; Marcinkeviciene, J.; Chang, S. Y.; Biller, S. A.; Kirby, M. S.; Parker, R. A.; Hamann, L. G. 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 J. Med. Chem. 2005, 48, 5025-5037
17. Tahrani, A. A.; Piya, M. K.; Barnett, A. H. Saxagliptin: a new DPP-4 inhibitor for the treatment of type 2 diabetes mellitus Adv. Ther. 2009, 26, 249-262
18. Deacon, C. F.; Holst, J. J. Saxagliptin: a new dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes Adv. Ther. 2009, 26, 488-499
19. Aertgeerts, K.; Ye, S.; Shi, L.; Prasad, S. G.; Witmer, D.; Chi, E.; Sang, B.-C.; Wijnands, R. A.; Webb, D. R.; Swanson, R. V. N-Linked glycosylation of dipeptidyl peptidase IV (CD26): effects on enzyme activity, homodimer formation, and adenosine deaminase binding Protein Sci. 2004, 13, 145-154
20. Aertgeerts, K.; Ye, S.; Tennant, M. G.; Kraus, M. L.; Rogers, J.; Sang, B.-C.; Skene, R. J.; Webb, D. R.; Prasad, G. S. Crystal structure of dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation Protein Sci. 2004, 13, 412-421
21. MFCD01959458.
22. PDB code 3G0C.
23. Himmelsbach, F.; Mark, M.; Eckhardt, M.; Langkopf, E.; Maier, R.; Lotz, R. World Patent 2002068420, 2002.
24. PDB code 3G0D.
25. Feng, J.; Zhang, Z.; Wallace, M. B.; Stafford, J. A.; Kaldor, S. W.; Kassel, D. B.; Navre, M.; Shi, L.; Skene, R. J.; Asakawa, T.; Takeuchi, K.; Xu, R.; Webb, D. R.; Gwaltney, S. L. Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV J. Med. Chem. 2007, 50, 2297-2300
26. Liu, H.; Ko, S.-B.; Josien, H.; Curran, D. P. Selective N-functionalization of 6-substituted-2-pyridones Tetrahedron Lett. 1995, 36, 8917-8920
27. Gacek, M.; Undheim, K. Alkylated 2- and 4-thiouracils. Syntheses and HPLC separations Acta Chem. Scand., Ser. B 1982, 36, 15-18
28. Alonso, F.; Beletskaya, I. P.; Yus, M. Non-conventional methodologies for transition-metal catalyzed carbon-carbon coupling: a critical overview. Part 2: The Suzuki reaction Tetrahedron 2008, 64, 3047-3101
29. Yin, L.; Liebscher, J. Carbon-carbon coupling reactions catalyzed by heterogeneous palladium catalysts Chem. Rev. 2007, 107, 133-173
30. PDB code 3G0G.
31. Lankas, G. R.; Leiting, B.; Roy, R. S.; Eiermann, G. J.; Beconi, M. G.; Biftu, T.; Chan, C.-C.; Edmondson, S.; Feeney, W. P.; He, H.; Ippolito, D. E.; Kim, D.; Lyons, K. A.; Ok, H. O.; Patel, R. A.; Petrov, A. N.; Pryor, K. A.; Qian, X.; Reigle, L.; Woods, A.; Wu, J. K.; Zaller, D.; Zhang, X.; Zhu, L.; Weber, A. E.; Thornberry, N. A. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9 Diabetes 2005, 54, 2988-2994
32. For method of determining ex vivo DPP-4 inhibition in plasma, see the following: Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.; Burkey, B. F.; Dunning, B. E.; Kapa, P.; Mangold, B. L.; Russell, M. E.; Hughes, T. E. 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
33. PDB code 3G0B.
34. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. AM1: a new general purpose quantum mechanical molecular model J. Am. Chem. Soc. 1985, 107, 3902-3909
35. Version 8. Clark, T., University of Erlangen-Nuremberg, Germany.
36. Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.; Su, S.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. General atomic and molecular electronic structure system J. Comput. Chem. 1993, 14, 1347-1363
37. Tomasi, J.; Persico, M. Molecular interactions in solution: an overview of methods based on continuous distributions of the solvent Chem. Rev. 1994, 94, 2027-2094
38. Christopher, R.; Covington, P.; Davenport, M.; Fleck, P.; Mekki, Q.; Wann, E.; Karim, A. Pharmacokinetics, Pharmacodynamics and Tolerability of Multiple Doses of Alogliptin Benzoate (SYR-322), a Dipeptidyl Peptidase-IV Inhibitor, in Patients with Type 2 Diabetes. Presented at the 2007 American Diabetes Association Meeting, Chicago, IL, United States, June 22-26, 2007; 499-P.
39. DeFronzo, R.; Fleck, P.; Wilson, C.; Mekki, Q. Alogliptin Monotherapy Improves Glycemic Control in Patients with Type 2 Diabetes. Presented at the 2008 American Diabetes Association Meeting, San Francisco, CA, United States, June 6-10, 2008; 446-P.
40. Fleck, P.; Christopher, R.; Covington, P.; Wilson, C.; Mekki, Q. Efficacy and Safety of Alogliptin Monotherapy in Patients with Type 2 Diabetes. Presented at the 2008 American Diabetes Association Meeting, San Francisco, CA, United States, June 6-10, 2008; 479-P.
41. DeLano, W. L. The PyMOL Molecular Graphics System; DeLano Scientific: San Carlos, CA, 2002; http://www.pymol.org.
42. Lee, J. W.; Chae, J. S.; Kim, C. S.; Kim, J. K.; Lim, D. S.; Shon, M. K.; Choi, Y. S.; Lee, S. H. World Patent 199605177, 1996.
43. Bantle, G. W.; Elworthy, T. R.; Guzman, A.; Jaime-Figueroa, S.; Lopez-Tapia, F. J.; Morgans, D. J., Jr.; Perez-Medrano, A.; Pfister, J. R.; Sjogren, E. B.; Talamas, F. X. European Patent 0748800, 2001.
44. Elmoghayar, M. R.; Groth, P.; Undheim, K. Nickel-catalyzed addition or coupling reactions of Grignard reagents with halopyrimidines Acta Chem. Scand., Ser. B 1983, 37, 109-114
45. Bang, C.-S.; Kim, Y.-Z.; Yeo, J.-H.; Lim, J.-C.; Oh, H.-S.; Woo, Y.-M.; Yang, D.-H.; Kim, S.-S.; Yim, H.-J. European Patent 0604920, 1994.
46. Beaton, H.; Hamley, P.; Tinker, A. C. The synthesis of 1-aminodihydroisoquinolines by an imine addition-cyclisation reaction Tetrahedron Lett. 1998, 39, 1227-1230