Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.

Abstract

In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).

Cite this paper

@article{Meyer2001StructureactivitySF, title={Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.}, author={Micael De Meyer and Robert J. Altenbach and Houqiao Bai and Fatima Z. Basha and William A. Carroll and James F Kerwin and S A Lebold and Edward L. Lee and John K Pratt and Kevin B Sippy and Kathleen Tietje and Michael D Wendt and Michael E. Brune and Steven A. Buckner and Arthur A. Hancock and Irene Drizin}, journal={Journal of medicinal chemistry}, year={2001}, volume={44 12}, pages={1971-85} }