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Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis

Velcicky, Juraj and Miltz, Wolfgang and Oberhauser, Berndt and Orain, David and Vaupel, Andrea and Weigand, Klaus and Dawson King, Janet and Littlewood-Evans, Amanda and Nash, Mark and Feifel, Roland and Loetscher, Pius (2017) Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis. Journal of Medicinal Chemistry. ISSN 0022-26231520-4804

Abstract

A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While compound 1a showed promising efficacy in several disease models, its binding to a H3 receptor as well as a hERG channel prevented it from further development. Therefore, a new round of optimization addressing the key liabilities was performed and led to discovery of compound 13 with an improved profile. Compound 13 showed significant efficacy in the rat antigen induced arthritis as well as in the hyperalgesia and angiogenesis model at a well-tolerated dose of 30 mg/kg.

Item Type: Article
Keywords: GPR4, GPCR, hERG, H3, autoimmune diseases, arthritis, pain, angiogenesis
Date Deposited: 29 Apr 2017 00:45
Last Modified: 29 Apr 2017 00:45
URI: https://oak.novartis.com/id/eprint/31016

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