BENZAZEPINONE CALCIUM-CHANNEL BLOCKERS .5. EFFECTS ON ANTIHYPERTENSIVE ACTIVITY ASSOCIATED WITH N1 AND AROMATIC SUBSTITUENTS

We have shown that the pyrrolidinylmethyl substituent on the lactam nitrogen (Nl) of benzazepinone and benzothiazepinone calcium channel blocking agents is resistant to metabolic deamination and generally increases the duration and potency of antihypertensive activity in spontaneously hypertensive rats (SHR) relative to (N,N-dimethylamino) ethyl analogs. Additionally, compounds possessing a substituent on the fused aromatic ring are more resistant to metabolic deacylation of the C3 hydroxy function, which may explain why aromatic substituents also frequently increase the potency and/or duration of antihypertensive activity. Our data also indicate the in antihypertensive activity associated with these structural modifications is independent of any effects of potency in vitro. Overall, we interpret these results to indicate that these structural modifications improve antihypertensive activity as a result of increased metabolic stability and, consequently, oral bioavailability.