GPR4 was found as an orphan GPCR highly expressed in the lung tissues, and reported to be activated by acidification in 2003. The activation of GPR4 is thought to lead some inflammatory events such as the production of chemokines and the neutrophil migration. Using a luciferase-reporter assay system detecting the constitutive activity of GPR4, we discovered a small-molecule GPR4 antagonist 1 , which inhibited the neutrophilic chemokine production and the following neutrophil migration in mouse lung injury model.However, compound 1  is metabolically unstable in human liver microsomes and induces QT prolongation, presumably due to high lipophilicity of its core structure: dibenzo[b,f]azepine. Therefore, we have explored scaffold-hopping to solve these issues and found a series of cyclohexylaniline-based novel GPR4 antagonists. Herein we will discuss the synthesis and SAR of these derivatives, leading to K-992  with improved pharmacokinetics and promising pharmacological properties.

Discovery of novel antagonists for proton-sensing receptor GPR4 and their pharmacological activities

248th National Meeting (2014)

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