Design and synthesis of piperazinylpyridine derivatives as novel 5-HT1A agonists/5-HT3 antagonists for the treatment of irritable bowel syndrome (IBS).

We have prepared a series of piperazinylpyridine derivatives for the treatment of irritable bowel syndrome (IBS). These compounds, which were designed by pharmacophore analysis, bind to both serotonin subtype 1A (5-HT1A) and subtype 3 (5-HT3) receptors. The nitrogen atom of the isoquinoline, a methoxy group and piperazine were essential to the pharmacophore for binding to these receptors. We also synthesized furo- and thienopyridine derivatives according to structure-activity relationship analyses. Compound 17c (TZB-20810) had high affinities to these receptors and exhibited 5-HT1A agonistic activity and 5-HT3 antagonistic activity concurrently, and is a promising drug for further development in the treatment of IBS.