(Phenylpiperazinyl)cyclohexylureas: Discovery of α1a/1d-selective adrenergic receptor antagonists for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS)

Benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) can be effectively treated with α1 adrenergic receptor antagonists. Unfortunately, currently marketed α1 blockers produce CV-related side effects that are caused by the subtype non-selective nature of the drugs. To overcome this problem, it was postulated that an α1a/1d subtype-selective antagonist would bring more benefit for the treatment of BPH/LUTS. As a continuation of our effort to develop selective α1a/1d ligands, a series of (phenylpiperazinyl)cyclohexylureas was synthesized and evaluated for the ability to bind to three cloned human α1-adrenergic receptor subtypes. Several trans isomers were shown to have equal affinity for both α1a, and α1d subtypes, with 14- to 47-fold selectivity versus the α1b subtype and >15-fold selectivity versus dopamine D2.