Synthesis and gastrointestinal prokinetic activity of novel benzamide derivatives with amphoteric side chains.
Novel benzamide derivatives (19-24, 32a-c, 43d-f), each possessing a cycloaminoalkanecarboxylic acid side chain, were synthesized and their gastrointestinal prokinetic and dopamine D2 receptor antagonist activities were evaluated. 4-[(4-Amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetic acid (19) exhibited the most potent gastro- and colon-prokinetic activities, through intravenous administration to conscious dogs, and also showed the reduced dopamine D2 receptor antagonistic activity. However, 19 showed only weak gastrointestinal prokinetic activity after oral administration. Several ester prodrugs (44-62) of 19 were tested for pharmacological activities as well as physicochemical and metabolic stability; the butyl ester (46) was consequently selected as a promising gastrointestinal prokinetic agent with reduced side effects.
Sakaguchi
J
J
Research Division, Hokuriku Seiyaku Co., Ltd., Katsuyama, Fukui, Japan. jun.sakaguchi@hokuriku-seiyaku.co.jp
Iwsaki
N
N
Iwanaga
Y
Y
Saito
T
T
Takahara
E
E
Kato
H
H
Hanaoka
M
M
D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003106:Colon / Q000187:drug effects; D004285:Dogs; D004639:Emetics / Q000138:chemical synthesis / Q000494:pharmacology; D005289:Ferrets; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008968:Molecular Conformation; D011355:Prodrugs; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D044422:Receptors, Serotonin, 5-HT4; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects; D013329:Structure-Activity Relationship
D001549:Benzamides; D004639:Emetics; D011355:Prodrugs; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4