Pyrrolobenzothiazines: Synthesis, Structure-Activity Relationships, Molecular Modeling Studies, and Cardiovascular Activity

Article abstract of DOI:10.1021/jm00022a005

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 IC50s for inhibition of <3H>nitrendipine binding calculated by radioreceptor assay on rat cortex and rat heart homogenates showed that some of the described compounds posesses an affinity equal to or higher than those of the reference calcium antagonists verapamil and cis-(+)-diltiazem.Furthermore, the alternation of the benzothiazepine system of diltiazem to the pyrrolo<1,4>-benzothiazine system of the title compounds resulted in a clear-cut selectivity 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 on isolated pig left atrium, revealed that the compounds examined displayed higher selectivity than the reference standard, within a wide variation of data.A number of structure-activity relationships trends have been identified, and possible explanation is advanced in order to account for the observed differences in selectivity.Prerequisite for in vitro calcium channel-blocking activity in the presence of two pharmacophores, namely, the substitution at C-4 and the substitution on the pyrrole ring.Two of the tested compounds, 8b and 28a, were identified as potent calcium antagonists selective for cardiac over vascular tissue.