(Phenylpiperazinyl)cyclohexylureas: discovery of alpha1a/1d-selective adrenergic receptor antagonists for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS).

Abstract

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).

• Authors: George Chiu, Shengjian Li, Peter J Connolly, Virginia Pulito, Jingchun Liu, Steven A Middleton
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 2 Pg. 640-4 (Jan 15 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 18055202 (Publication Type: Journal Article)

Chemical References

• ADRA1D protein, human
• Adrenergic alpha-1 Receptor Antagonists
• Receptors, Adrenergic, alpha-1
• Urea

Topics

• Adrenergic alpha-1 Receptor Antagonists
• Humans
• Male
• Prostatic Hyperplasia (drug therapy)
• Receptors, Adrenergic, alpha-1
• Structure-Activity Relationship
• Urea (chemistry, pharmacology, therapeutic use)