Design and synthesis of orally active benzamide derivatives as potent serotonin 4 receptor agonist

• Published in: Bioorganic & medicinal chemistry 2003-09, Vol.11 (19), p.4225-4234
• Main Authors: Sonda, Shuji, Kawahara, Toshio, Murozono, Takahiro, Sato, Noriko, Asano, Kiyoshi, Haga, Keiichiro
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antidepressive Agents - chemical synthesis; Antidepressive Agents - pharmacology; Benzamides - chemical synthesis; Benzamides - pharmacology; Binding, Competitive; Biological and medical sciences; Drug Design; Gastrointestinal Motility - drug effects; Guinea Pigs; Inhibitory Concentration 50; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists - chemical synthesis; Serotonin Receptor Agonists - pharmacology; Serotoninergic system; Stimulation, Chemical; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(03)00412-7

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. 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.