Synthesis and Pharmacological Evaluation of 1-Isopropyl-1,2,3,4-tetrahydroisoquinoline Derivatives as Novel Antihypertensive Agents

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概要

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• A series of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and their bradycardic activities were evaluated in isolated guinea pig right atria. Structure–activity relationship studies revealed that the introduction of an appropriate substituent and its position on the 1,2,3,4-tetrahydroisoquinoline ring are essential for potent in vitro activity. Furthermore, the tether between the piperidyl moiety and the terminal aromatic ring is important for potent antihypertensive activity. Oral administration of 6-fluoro-1-isopropyl-2-{[1-(2-phenylethyl)piperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline (3b) to spontaneously hypertensive rats (SHR) elicited antihypertensive effects 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.

• Tomura Yuichi

  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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