(Phenylpiperazinyl)cyclohexylureas: discovery of alpha1a/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 alpha(1) adrenergic receptor antagonists. Unfortunately, currently marketed alpha(1) 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 alpha(1a/1d) subtype-selective antagonist would bring more benefit for the treatment of BPH/LUTS. As a continuation of our effort to develop selective alpha(1a/1d) ligands, a series of (phenylpiperazinyl)cyclohexylureas was synthesized and evaluated for the ability to bind to three cloned human alpha(1)-adrenergic receptor subtypes. Several trans isomers were shown to have equal affinity for both alpha(1a), and alpha(1d) subtypes, with 14- to 47-fold selectivity versus the alpha(1b) subtype and >15-fold selectivity versus dopamine D(2).
Johnson & Johnson Pharmaceutical Research and Development L.L.C., PO Box 300, 1000 Route 202 South, Raritan, NJ 08869, USA. George.Chiu@sanofi-aventis.com
George
G
Chiu
Shengjian
S
Li
Peter J
PJ
Connolly
Virginia
V
Pulito
Jingchun
J
Liu
Steven A
SA
Middleton
D058668:Adrenergic alpha-1 Receptor Antagonists; D006801:Humans; D008297:Male; D011470:Prostatic Hyperplasia / Q000188:drug therapy*; D018340:Receptors, Adrenergic, alpha-1; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
C547719:ADRA1D protein, human; D058668:Adrenergic alpha-1 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D014508:Urea