2-({6-[(3R)-3-氨基-3-甲基哌啶-1-基]-1,3-二甲基-2,4-二氧代-1,2,3,4-四氢-5H-吡咯并[3,2-d]嘧啶-5-基}甲基)-4-氟苯甲腈（DSR-12727）：一种强效、口服活性的二肽基肽酶 IV 抑制剂，不会导致 CYP3A 的基于机制的失活。
2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727): a potent, orally active dipeptidyl peptidase IV inhibitor without mechanism-based inactivation of CYP3A.
机构信息
Drug Research Division, Dainippon Sumitomo Pharma Co. Ltd, 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan.
出版信息
Bioorg Med Chem. 2011 Sep 15;19(18):5490-9. doi: 10.1016/j.bmc.2011.07.042. Epub 2011 Aug 4.
We report on the identification of 2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727) (7a) as a potent and orally active DPP-4 inhibitor without mechanism-based inactivation of CYP3A. Compound 7a showed good DPP-4 inhibitory activity (IC(50)=1.1 nM), excellent selectivity against related peptidases and other off-targets, good pharmacokinetic and pharmacodynamic profile, great in vivo efficacy in Zucker-fatty rat, and no safety concerns both in vitro and in vivo.
我们报告了 2-({6-[(3R)-3-氨基-3-甲基哌啶-1-基]-1,3-二甲基-2,4-二氧代-1,2,3,4-四氢-5H-吡咯并[3,2-d]嘧啶-5-基}甲基)-4-氟苯甲腈（DSR-12727）（7a）的鉴定，这是一种有效的、具有口服活性的 DPP-4 抑制剂，不会导致 CYP3A 发生基于机制的失活。化合物 7a 表现出良好的 DPP-4 抑制活性（IC50=1.1 nM），对相关肽酶和其他非靶标具有优异的选择性，良好的药代动力学和药效学特性，在 Zucker-fatty 大鼠中具有很好的体内疗效，并且在体外和体内均无安全性问题。
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