PYRROLO[2,1-C][1,4] BENZOTHIAZINES - SYNTHESIS, STRUCTURE-ACTIVITY-RELATIONSHIPS, MOLECULAR MODELING STUDIES, AND CARDIOVASCULAR ACTIVITY

The synthesis and pharmacological evaluation of a series of pyrrolo[1, 4]benzothiazine derivatives are described. These compounds, related to diltiazem, have been shown to be representative of a novel series of calcium channel antagonists. The IC(50)s for inhibition of [H-3]nitren dipine binding calculated by radioreceptor assay on rat cortex and rat heart homogenates showed that some of the described compounds possess an affinity equal to or higher than those of the reference calcium an tagonists verapamil and cis-(+)-diltiazem. Furthermore, the alteration of the benzothiazepinone system of diltiazem to the pyrrolo[1,4]benzo thiazine system of the title compounds resulted in a clear-cut selecti vity for cardiac over vascular tissue, as shown in functional studies. In fact comparison of calcium antagonist activity on guinea pig aorta strips with the negative inotropic activity, determined by using an i solated guinea pig left atrium, revealed that the compounds examined d isplayed higher selectivity than the reference standard, within a wide variation of data. A number of structure-activity relationship trends have been identified, and possible explanation is advanced in order t o account for the observed differences in selectivity. Prerequisite fo r in vitro calcium channel-blocking activity is the presence of two ph armacophores, namely, the substitution at C-4 and the substitution on the pyrrole ring. Two of the tested compounds, 8b and 28a, were identi fied as potent calcium antagonists selective for cardiac over vascular tissue.