title: 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.
abstract: 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.
authors.affiliation: Dong-A ST Research Institute, Yongin 446-905, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: pjs2002@donga.co.kr.
authors.forename: Jung Sang
authors.initials: JS
authors.lastname: Park
authors.affiliation: Dong-A ST Research Institute, Yongin 446-905, Republic of Korea.
authors.forename: Weonbin
authors.initials: W
authors.lastname: Im
authors.affiliation: Dong-A ST Research Institute, Yongin 446-905, Republic of Korea.
authors.forename: Sunghak
authors.initials: S
authors.lastname: Choi
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Sook Jin
authors.initials: SJ
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jun Min
authors.initials: JM
authors.lastname: Jung
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Ki Seon
authors.initials: KS
authors.lastname: Baek
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Han Pyo
authors.initials: HP
authors.lastname: Son
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Satyasheel
authors.initials: S
authors.lastname: Sharma
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: In Su
authors.initials: IS
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: yhjung@skku.edu.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Jung
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005746:Gastric Emptying / Q000187:drug effects*; D006801:Humans; D008297:Male; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010880:Piperidines; D058828:Serotonin 5-HT4 Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4
keywords: 5-HT(4); GI disorder; Gastric emptying rate; Prokinetic; hERG inhibition