3-Substituted 3-(4-aryloxyaryl)-propanoic acids as GPR40 agonists |
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Authors: | Walsh Shawn P Severino Alexandra Zhou Changyou He Jiafang Liang Gui-Bai Tan Carina P Cao Jin Eiermann George J Xu Ling Salituro Gino Howard Andrew D Mills Sander G Yang Lihu |
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Affiliation: | Merck Research Laboratories, Merck & Co., Inc., 126 E. Lincoln Ave., PO Box 2000, Rahway, NJ 07065-0900, USA |
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Abstract: | The design, synthesis, and structure-activity relationship (SAR) for a series of β-substituted 3-(4-aryloxyaryl)propanoic acid GPR40 agonists is described. Systematic replacement of the pendant aryloxy group led to identification of potent GPR40 agonists. In order to identify candidates suitable for in vivo validation of the target, serum shifted potency and pharmacokinetic properties were determined for several compounds. Finally, further profiling of compound 7 is presented, including demonstration of enhanced glucose tolerance in an in vivo mouse model. |
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Keywords: | GPR40 Agonist 3-(4-Aryloxy)-propanoic acids Diabetic GDIS |
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