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Synthesis and Gastrointestinal Prokinetic Activity of Novel Benzamide Derivatives with Amphoteric Side Chains.

2001; Pharmaceutical Society of Japan; Volume: 49; Issue: 4 Linguagem: Inglês

10.1248/cpb.49.424

1347-5223

Jun Sakaguchi, Nobuhiko Iwasaki, Yuji Iwanaga, Takaharu Saito, Eiji Takahara, Hideo Kato, Miyoji Hanaoka,

Pharmacological Receptor Mechanisms and Effects

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.