Structure−Activity Studies for a Novel Series of Tricyclic Substituted Hexahydrobenz[e]isoindole α<INF>1A</INF> Adrenoceptor Antagonists as Potential Agents for the Symptomatic Treatment of Benign Prostatic Hyperplasia (BPH)

In search of a uroselective agent that exhibits a high level of selectivity for the α<INF>1A</INF> receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the α<INF>1</INF> adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.