title: Design and synthesis of orally active benzamide derivatives as potent serotonin 4 receptor agonist.
abstract: A series of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide derivatives bearing an aralkylamino, alkylamino, benzoyl or phenylsulfonyl group at its side chain part at the 1-position on the piperidine ring was synthesized. They were evaluated for serotonin 4 (5-HT(4)) receptor agonist activity by testing their ability to contract the isolated guinea-pig ascending colon. 4-Amino-5-chloro-2-methoxy-N-[1-[5-(1-methylindol-3-ylcarbonylamino)pentyl]piperidin-4-ylmethyl]benzamide (1a, Y-34959) and its related compounds possessed favorable pharmacological profiles for gastrointestinal motility. Unfortunately, the compound 1a showed low bioavailability when given orally presumably due to its poor intestinal absorption rate. Replacement of the 1-methylindol-3-yl carbonylamino moiety of 1a with an aralkylamino (or alkylamino) group did not improve the intestinal absorption rate. Replacement of the 1-methylindol-3-ylcarbonylamino moiety with a benzoyl or phenylsulfonyl group increased the intestinal absorption rate compared with 1a. These compounds revealed good pharmacological profiles for gastrointestinal motility and were superior to 1a in oral bioavailability.
authors.affiliation: Pharmaceutical Development Laboratories, Technology & Production Division, Mitsubishi Pharma Corporation, 955, 871-8550, Koiwai, Yoshitomi-cho, Chikujo-gun Fukuoka, Japan. sonda.shuuji@ma.m-pharma.co.jp
authors.forename: Shuji
authors.initials: S
authors.lastname: Sonda
authors.forename: Toshio
authors.initials: T
authors.lastname: Kawahara
authors.forename: Takahiro
authors.initials: T
authors.lastname: Murozono
authors.forename: Noriko
authors.initials: N
authors.lastname: Sato
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Asano
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Haga
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D015195:Drug Design; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D001549:Benzamides; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists