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Design of potent and selective GPR119 agonists for type II diabetes |
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| Authors: | Szewczyk Jason W Acton John Adams Alan D Chicchi Gary Freeman Stanley Howard Andrew D Huang Yong Li Cai Meinke Peter T Mosely Ralph Murphy Elizabeth Samuel Rachel Santini Conrad Yang Meng Zhang Yong Zhao Kake Wood Harold B |
| Institution: | a Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000 Rahway, NJ 07065, USA b Lead Optimization Pharmacology, Merck & Co., Inc., PO Box 2000 Rahway, NJ 07065, USA c Preclinical Drug Metabolism and Pharmacokinetics, Merck & Co., Inc., PO Box 2000 Rahway, NJ 07065, USA |
| Abstract: | Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC50 = 3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58). |
| Keywords: | GPR119 agonist GPCR Diabetes GDIS |
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