Discovery and SAR of N-(1-((substituted piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl)-2-methoxybenzamide derivatives: 5-Hydroxytryptamine receptor 4 agonist as a potent prokinetic agent

• Published in: European journal of medicinal chemistry Vol. 109; pp. 75 - 88
• Main Authors: Park, Jung Sang, Im, Weonbin, Choi, Sunghak, Park, Sook Jin, Jung, Jun Min, Baek, Ki Seon, Son, Han Pyo, Sharma, Satyasheel, Kim, In Su, Jung, Young Hoon
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 15.02.2016; Elsevier
• Subjects: 5-HT4; Animals; Benzamides - chemistry; Benzamides - pharmacology; Chemistry, Medicinal; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - metabolism; Gastric Emptying - drug effects; Gastric emptying rate; GI disorder; hERG inhibition; Humans; Life Sciences & Biomedicine; Male; Pharmacology & Pharmacy; Piperidines - chemistry; Piperidines - pharmacology; Prokinetic; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4 - metabolism; Science & Technology; Serotonin 5-HT4 Receptor Agonists - chemistry; Serotonin 5-HT4 Receptor Agonists - pharmacology; Structure-Activity Relationship; 5-HT4; Prokinetic; GI disorder; hERG inhibition; Gastric emptying rate; PATHWAYS; CONSTIPATION; RAT; EFFICACY; PERISTALTIC REFLEX; CISAPRIDE; GUINEA-PIG INTESTINE; FUNCTIONAL DYSPEPSIA; SEROTONIN; 5-HT
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.12.006

A series of novel benzamide derivatives, altering the 4-fluorophenylalkyl moiety in cisapride, were synthesized as 5-HT4 receptor agonists, and SAR of these analogs was examined on in vitro and in vivo prokinetic activities. These compounds were synthesized for high 5-HT4 receptor binding affinities and low hERG affinities. Several types of analogs were obtained and screened for 5-HT4 binding, hERG blocking, agonism, and gastric emptying assessment. Among the analogues, compound 23g showed promising results compared with the other analogs with respect to gastric emptying rates in rats. Therefore, we suggest that it may be a clinical candidate for the development of a potent prokinetic agent to treat GI disorders. [Display omitted] •26 Novel benzamide derivatives of cisapride were synthesized as potential prokinetic agents.•Alkyl piperidinyl moieties showed good binding affinities for the 5-HT4 receptor and low affinities for hERG.•Compound 23g could be a good candidate to treat GI disorders, particularly functional dyspepsia.