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Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists

Authors :
Run Zhuang
Qi Guo
Xianyun Jiao
Thanhvien Tran
Jonathan B. Houze
Frank Li
Paul John Dransfield
Jane Zhang
Jiwen Jim Liu
Richard V. Connors
Yongli Su
Jian Luo
Julio C. Medina
Marc Vimolratana
Xiaohui Du
Gayathri Swaminath
An-Rong Li
Ming Yu
Liusheng Zhu
Sean P. Brown
Todd J. Kohn
Zhongyu Wang
Yingcai Wang
Daniel C.-H. Lin
Simon Wong
Source :
ACS Medicinal Chemistry Letters. 5:384-389
Publication Year :
2014
Publisher :
American Chemical Society (ACS), 2014.

Abstract

We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties.

Details

ISSN :
19485875
Volume :
5
Database :
OpenAIRE
Journal :
ACS Medicinal Chemistry Letters
Accession number :
edsair.doi.dedup.....06439f1cb4f3cdf9f6fcdb67b8a2cf08
Full Text :
https://doi.org/10.1021/ml4005123