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

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.

SUBMITTER: Liu P

PROVIDER: S-EPMC4538435 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Liu Ping P Hu Zhiyong Z DuBois Byron G BG Moyes Christopher R CR Hunter David N DN Zhu Cheng C Kar Nam Fung NF Zhu Yuping Y Garfunkle Joie J Kang Ling L Chicchi Gary G Ehrhardt Anka A Woods Andrea A Seo Toru T Woods Morgan M van Heek Margaret M Dingley Karen H KH Pang Jianmei J Salituro Gino M GM Powell Joyce J Terebetski Jenna L JL Hornak Viktor V Campeau Louis-Charles LC Lamberson Joe J Ujjainwalla Fez F Miller Michael M Stamford Andrew A Wood Harold B HB Kowalski Timothy T Nargund Ravi P RP Edmondson Scott D SD

ACS medicinal chemistry letters 20150710 8

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 prop ...[more]

PMID: 26288697

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

Publications

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

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