1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine:: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties

被引:535
作者
Villhauer, EB
Brinkman, JA
Naderi, GB
Burkey, BF
Dunning, BE
Prasad, K
Mangold, BL
Russell, ME
Hughes, TE
机构
[1] Novartis Inst Biomed Res, Dept Chem, E Hanover, NJ 07936 USA
[2] Novartis Inst Biomed Res, Metab Dis Pharmacol Dept, E Hanover, NJ 07936 USA
[3] Novartis Inst Biomed Res, Drug Metab & Pharmacokinet Dept, E Hanover, NJ 07936 USA
关键词
D O I
10.1021/jm030091l
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure-activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, axe described as well as the path that led from clinical development compound 1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP-LAF237, 12j). The pharmacological profile of 12j in obese Zucker fa/fa rats along with pharmacokinetic profile comparison of 8c and 12j in normal cynomolgus monkeys is discussed. The results suggest that 12j is a potent, stable, selective DPP-IV inhibitor possessing excellent oral bioavailability and potent antihyperglycemic activity with potential for once-a-day administration.
引用
收藏
页码:2774 / 2789
页数:16
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