| Literature DB >> 26288697 |
Ping Liu1, Zhiyong Hu1, Byron G DuBois1, Christopher R Moyes1, David N Hunter1, Cheng Zhu1, Nam Fung Kar1, Yuping Zhu1, Joie Garfunkle1, Ling Kang1, Gary Chicchi1, Anka Ehrhardt1, Andrea Woods1, Toru Seo1, Morgan Woods1, Margaret van Heek1, Karen H Dingley1, Jianmei Pang1, Gino M Salituro1, Joyce Powell1, Jenna L Terebetski1, Viktor Hornak1, Louis-Charles Campeau1, Joe Lamberson1, Fez Ujjainwalla1, Michael Miller1, Andrew Stamford1, Harold B Wood1, Timothy Kowalski1, Ravi P Nargund1, Scott D Edmondson1.
Abstract
We report herein the design and synthesis of a series of potent and selective GPR119 agonists. Our objective was to develop a GPR119 agonist with properties that were suitable for fixed-dose combination with a DPP4 inhibitor. Starting from a phenoxy analogue (1), medicinal chemistry efforts directed toward reducing half-life and increasing solubility led to the synthesis of a series of benzyloxy analogues. Compound 28 was chosen for further profiling because of its favorable physicochemical properties and excellent GPR119 potency across species. This compound exhibited a clean off-target profile in counterscreens and good in vivo efficacy in mouse oGTT.Entities:
Keywords: GPR119 agonists; Type II diabetes; benzyloxy analogues; chiral cis-cyclopropanes; oGTT
Year: 2015 PMID： 26288697 PMCID： PMC4538435 DOI： 10.1021/acsmedchemlett.5b00207
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345