1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine:: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties
1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine:: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties
复制标题
DOI：
10.1021/jm030091l
复制
发表时间：
2003-06-19
影响因子：
7.3
通讯作者：
Hughes, TE
中科院分区：
文献类型：
--
作者：
Villhauer, EB;Brinkman, JA;Hughes, TE
二肽基肽酶 IV (DPP-IV) 抑制有可能成为 2 型糖尿病的有价值的治疗方法。描述了新型 DPP-IV 抑制剂 N-取代-甘氨酰-2-氰基吡咯烷的合成和构效关系，以及从临床开发化合物 1-[2-[5-氰基吡啶-2-基)氨基]乙基氨基]乙酰基-2-氰基-(S)-吡咯烷 (NVP-DPP728, 8c) 到其后续产品的路径， 1-[[(3-羟基-1-金刚烷基)氨基]乙酰基]-2-氰基-(S)-吡咯烷(NVP-LAF237，12j)。讨论了 12j 在肥胖 Zucker fa/fa 大鼠中的药理学特征以及 8c 和 12j 在正常食蟹猴中的药代动力学特征比较。结果表明，12j 是一种有效、稳定、选择性的 DPP-IV 抑制剂，具有优异的口服生物利用度和有效的降血糖活性，适合每天一次给药。
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.