Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization
We previously reported a highly?potent?DPP-IV?inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a?pharmacokinetic?property-driven?optimization?to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with?pyrrolopyrimidine?(21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of the?pyrrolopyrimidine?scaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development. (C) 2012 Elsevier Masson SAS. All rights reserved.
We previously reported a highlypotentDPP-IVinhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated apharmacokineticproperty-drivenoptimizationto improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine withpyrrolopyrimidine(21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of thepyrrolopyrimidinescaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development. (C) 2012 Elsevier Masson SAS. All rights reserved.
Zeng, LL(Zeng, Lili)、Xu, HJ (Xu, Hongjiang)、Yang, L (Yang, Ling)、Cheng, N (Cheng, Na)、Zhao, X (Zhao, Xin)、Zeng, SG(Zeng, Shaogao)、Li, ZY (Li, Zhiyuan)、Zhao, JL (Zhao, Junling)、Zhang, GC (Zhang, Guicheng)、Tu, ZC (Tu, Zhengchao)、Zhang, XQ (Zhang, Xiquan)、Huang, M (Huang, Min)、Xie, H(Xie, Hui)、Hu, WH (Hu, Wenhui)、Lu, X (Lu, Xin)
药学基础医学生物化学
PP-IV inhibitorType 2 diabetesPK-driven optimizationPyrrolopyrimidine analoguesOral glucose tolerance test
Zeng, LL(Zeng, Lili),Xu, HJ (Xu, Hongjiang),Yang, L (Yang, Ling),Cheng, N (Cheng, Na),Zhao, X (Zhao, Xin),Zeng, SG(Zeng, Shaogao),Li, ZY (Li, Zhiyuan),Zhao, JL (Zhao, Junling),Zhang, GC (Zhang, Guicheng),Tu, ZC (Tu, Zhengchao),Zhang, XQ (Zhang, Xiquan),Huang, M (Huang, Min),Xie, H(Xie, Hui),Hu, WH (Hu, Wenhui),Lu, X (Lu, Xin).Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization[EB/OL].(2017-11-17)[2025-08-02].https://chinaxiv.org/abs/201711.02419.点此复制
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