Discovery of novel 4-methylpiperidinyl benzamide derivatives as 5-HT4 receptor agonist for the treatment of gastrointestinal disorders

Novel 4-methypiperidinyl benzamide derivatives were synthesized and evaluated for in vitro and in vivo prokinetic activities. In these derivatives, 3-methoxypiperidine moiety of norcisapride, a pharmacophore of cisapride and DA-6650, were replaced to 4-methylpiperidinyl moiety without chiral center. Among these derivatives, Compound 28b had a potent 5-HT4 receptor-binding affinity (IC50 = 0.067 mu M) and improved safety profiles without inhibiting CYP3A4 (IC50 = 7.272 mu M) and blocking human ether-a-go-go-related gene (hERG) channel (IC50 > 10 mu M). In vivo rat models, Compound 28b enhanced gastric emptying rate (68.2%) and showed over twofold increased defecation weight compared to the control. Moreover, it showed the alleviation effect of visceral hypersensitivity in the irritation rat model. Thus, Compound 28b was selected preclinical candidate as a prokinetic agent with a favorable safety profile for treating gastrointestinal disorders.