Synthesis and Pharmacological Evaluation of 1-Alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide Derivatives as Novel Antihypertensive Agents

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概要

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• We synthesized and evaluated inhibitory activity against T-type Ca2+ channels for a series of 1-alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide derivatives. Structure–activity relationship studies have revealed that the isopropyl substituent at the benzylic position plays an important role in exerting potent inhibitory activity, and the absolute configuration of the benzylic position was found to be opposite that of mibefradil, which was first launched as a new class of T-type Ca2+ channel blocker. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-1-[2-(3-methoxyphenyl)ethyl]piperidine-4-carboxamide (17f) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, an adverse effect 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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