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

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.