Synthesis and Pharmacological Evaluation of 2-(1-Alkylpiperidin-4-yl)-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]acetamide Derivatives as Novel Antihypertensive Agents

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概要

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• 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 Ca2+ channels. Structure–activity relationship studies revealed that the position of the amide structure was important for the potent inhibitory activity toward T-type Ca2+ channels. In addition, the introduction of an appropriate substituent on the pendant benzene ring played a crucial role for the selectivity towards T-type Ca2+ channels over L-type Ca2+ 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 Ca2+ channels over L-type Ca2+ channels, lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca2+ channel blockers.

著者

• Ohta Mitsuaki

  Drug Discovery Research, Astellas Pharma Inc.

• Watanuki Susumu

  Drug Discovery Research, Astellas Pharma Inc.

• Matsuura Keisuke

  Drug Discovery Research, Astellas Pharma Inc.

• Okada Minoru

  Technology, Astellas Pharma Inc.

• Okazaki Toshio

  QA, RA and Pharmacovigilance, Astellas Pharma Inc.

• Tsukamoto Shin-ichi

  Drug Discovery Research, Astellas Pharma Inc.

• Tomura Yuichi

  Drug Discovery Research Astellas Pharma Inc.

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