Discovery of novel 4‐methylpiperidinyl benzamide derivatives as 5‐HT4 receptor agonist for the treatment of gastrointestinal disorders. (10th January 2023)

• Record Type: Journal Article
• Authors: Choi, Sunho; Lee, Min Jung; Ahn, Kwang‐Hyun
• Is Part Of: Bulletin of the Korean Chemical Society. Volume 44:Number 4(2023)
• Page Start: 370
• Page End: 379
• Publication Date: 2023-01-10
• Subjects: 5‐HT4 -- benzamide -- gastrointestinal disorder -- IBS‐C -- prokinetic; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/bkcs.12667
• Languages: English
• ISSNs: 0253-2964

Abstract

Abstract: 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 μM) and improved safety profiles without inhibiting CYP3A4 (IC50 = 7.272 μM) and blocking human ether‐à‐go‐go‐related gene (hERG) channel (IC50 > 10 μM). 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. Abstract : Novel series of 4‐methylpiperidinyl benzamide derivatives were synthesized and evaluated. Among them, Compound 28b showed potent 5‐HT4 receptor‐binding affinity. Moreover, Compound 28b had safety profiles without inhibiting CYP3A4 and blocking hERG. It also showed improved efficacies in animal models as a prokinetic agent.