New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation

Abstract

The syntheses and biological evaluation of a series of novel indeno[1,2-d]thiazole derivatives are described. Several groups reported 5-HT3 receptor agonists which were mainly evaluated for their activities on the von Bezold–Jarisch reflex (B–J reflex). We discovered that tetrahydrothiazolopyridine derivative 1b had a contractile effect on the isolated guinea pig colon with weak B–J reflex. Our efforts to find a new type of 5-HT3 receptor agonists on the isolated guinea pig colon focused on the synthesis of a fused thiazole derivative 1d modified from 1b and reverse-fused thiazole derivatives (7–10). In this series, 10f (YM-31636) showed high affinity and selectivity for the cloned human 5-HT3 receptor; furthermore, it showed potent and selective 5-HT3 receptor agonistic activity. YM-31636 was examined for its effects on defecation in animals, thus evaluating the compound as an agent against constipation.