Structure−Activity Studies for a Novel Series of Tricyclic Substituted Hexahydrobenz[e]isoindole α1A 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 1A 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 1 adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.