Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists

A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT3 receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT3A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT3 receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT3 receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).

The discovery of a novel series of benzoxazole-4-carboxamides is described. A structure–activity relationship study resulted in the identification of 2-amino benzoxazoles 41 and 48 as selective, orally bioavailable 5-HT3 receptor antagonists.Figure optionsDownload as PowerPoint slide