Benzazepinone calcium channel blockers. 2. Structure-activity and drug metabolism studies leading to potent antihypertensive agents. Comparison with benzothiazepinones.

As part of a program to discover potent antihypertensive analogues of diltiazem (3a), we prepared 1-benzazepin-2-ones (4). Benzazepinones competitively displace radiolabeled diltiazem, and show the same absolute stereochemical preferences at the calcium channel receptor protein. Derivatives of 4 containing a trifluoromethyl substituent in the fused aromatic ring show potent and long-acting antihypertensive activity. Studies of the metabolism of 4 lead to the metabolically stable antihypertensive calcium channel blockers 5a and 5c. Benzazepinone 5a is a longer acting and more potent antihypertensive agent than the second generation diltiazem analogue TA-3090 (3e).

Citation

D M Floyd, S D Kimball, J Krapcho, J Das, C F Turk, R V Moquin, M W Lago, K J Duff, V G Lee, R E White. Benzazepinone calcium channel blockers. 2. Structure-activity and drug metabolism studies leading to potent antihypertensive agents. Comparison with benzothiazepinones. Journal of medicinal chemistry. 1992 Feb 21;35(4):756-72

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PMID: 1542102

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