Abstract
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).
MeSH terms
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Acetylation
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Animals
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Antihypertensive Agents / chemical synthesis*
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Antihypertensive Agents / metabolism
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Antihypertensive Agents / therapeutic use
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Aorta / drug effects
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Aorta / physiology
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Benzazepines / chemical synthesis*
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Benzazepines / metabolism
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Benzazepines / therapeutic use
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Calcium Channel Blockers / chemical synthesis*
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Calcium Channel Blockers / metabolism
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Calcium Channel Blockers / therapeutic use
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Diltiazem / analogs & derivatives*
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Diltiazem / chemistry
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Diltiazem / therapeutic use
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Guinea Pigs
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Hypertension / drug therapy
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Male
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Microsomes, Liver / metabolism
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Molecular Conformation
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Molecular Structure
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Pyrrolidines / chemical synthesis
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Pyrrolidines / therapeutic use
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Rabbits
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Rats
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Rats, Inbred SHR
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Structure-Activity Relationship
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Vasodilation / drug effects
Substances
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Antihypertensive Agents
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Benzazepines
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Calcium Channel Blockers
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Pyrrolidines
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3-(acetyloxy)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(2-pyrrolidinylmethyl)-6-(trifluoromethyl)-2H-benzazepin-2-one
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Diltiazem