Synthesis and pharmacological evaluation of 2-(1-alkylpiperidin-4-yl)-N- [(1R)-1-(4-fluorophenyl)-2-methylpropyl]acetamide derivatives as novel antihypertensive agents

Abstract

We synthesized and evaluated the inhibitory activity of a series of 2-(1-alkylpiperidin-4-yl)-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]acetamide derivatives against T-type Ca 2+ channels. Structure-activity relationship studies revealed that the position of the amide structure was important for the potent inhibitory activity toward T-type Ca 2+ channels. In addition, the introduction of an appropriate substituent on the pendant benzene ring played a crucial role for the selectivity towards T-type Ca 2+ channels over L-type Ca 2+ channels and the potent bradycardic activity of these derivatives. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-2-(1-{2-[2-(2-methoxyethoxy)phenyl] ethyl}piperidin-4-yl)acetamide (4f), which had superior selectivity for T-type Ca 2+ channels over L-type Ca 2+ channels, lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca 2+ channel blockers. © 2012 The Pharmaceutical Society of Japan.