RESUMO
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).
Assuntos
Anti-Hipertensivos/síntese química , Benzazepinas/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Diltiazem/análogos & derivados , Acetilação , Animais , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/uso terapêutico , Aorta/efeitos dos fármacos , Aorta/fisiologia , Benzazepinas/metabolismo , Benzazepinas/uso terapêutico , Bloqueadores dos Canais de Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/uso terapêutico , Diltiazem/química , Diltiazem/uso terapêutico , Cobaias , Hipertensão/tratamento farmacológico , Masculino , Microssomos Hepáticos/metabolismo , Conformação Molecular , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/uso terapêutico , Coelhos , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacosRESUMO
As part of a program aimed at identifying novel analogues of diltiazem, we developed several synthetic routes for 3-alkylbenzazepinones, both in racemic and nonracemic form. Structure-activity relationship studies in this series have led to identification of several analogues as potent calcium channel blocking agents, both in vitro and in vivo. Analogues containing a 6-trifluoromethyl substituent (17a and 17b) are the most potent vasorelaxants in vitro. The oral antihypertensive activity of these compounds is comparable to its 3-acetoxy derivative 1 (X = 6-CF3) and 8-chlorodiltiazem (2b). The 3-allyl analogue 17c is a more potent antihypertensive agent than 17a, 17b, or 8-chlorodiltiazem (2b), and has a longer duration of action in vivo.
Assuntos
Anti-Hipertensivos/síntese química , Benzazepinas/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Animais , Anti-Hipertensivos/uso terapêutico , Aorta/efeitos dos fármacos , Aorta/fisiologia , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cobaias , Hipertensão/tratamento farmacológico , Masculino , Conformação Molecular , Estrutura Molecular , Músculos/metabolismo , Coelhos , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacos , Difração de Raios XRESUMO
We have synthesized a series of benzazepinones (2) in order to determine the structure-activity relationships (SAR) for calcium channel blockers related to diltiazem. A prerequisite for calcium channel blocking activity in vitro and in vivo is the presence of two pharmacophores: a 4'-aryl methyl ether and a basic substituent appended to N1 with a pKa in the physiological range. When these constraints are satisfied, a wide variety of substitution is tolerated at C6, C7, and C3. The presence of an electron-withdrawing group at C6 appears to enhance potency in vitro and in vivo. For such benzazepinones, activity is primarily dependent upon lipophilicity, as measured by log P. We believe these compounds must partition into the cell membrane in order to access their receptor. The quaternary methiodide 15k was used to demonstrate that the binding site for benzazepinones is on the intracellular face of the membrane. This work represents the first comprehensive SAR of diltiazem-like calcium channel blockers.
