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

A novel, selective, and efficacious GPR4 antagonist <b>13</b> was developed starting from lead compound <b>1a</b>. While compound <b>1a</b> showed promising efficacy in several disease models, its binding to a H<sub>3</sub> 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 <b>13</b> with an improved profile. Compound <b>13</b> 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.