Design of Potent and Orally Active GPR119 Agonists for the Treatment of Type II Diabetes

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...

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Published in:ACS medicinal chemistry letters 2015-08, Vol.6 (8), p.936-941
Main Authors: Liu, Ping, Hu, Zhiyong, DuBois, Byron G, Moyes, Christopher R, Hunter, David N, Zhu, Cheng, Kar, Nam Fung, Zhu, Yuping, Garfunkle, Joie, Kang, Ling, Chicchi, Gary, Ehrhardt, Anka, Woods, Andrea, Seo, Toru, Woods, Morgan, van Heek, Margaret, Dingley, Karen H, Pang, Jianmei, Salituro, Gino M, Powell, Joyce, Terebetski, Jenna L, Hornak, Viktor, Campeau, Louis-Charles, Lamberson, Joe, Ujjainwalla, Fez, Miller, Michael, Stamford, Andrew, Wood, Harold B, Kowalski, Timothy, Nargund, Ravi P, Edmondson, Scott D
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Language:English
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Letter
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Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.5b00207