(Arylpiperazinyl)cyclohexylsufonamides: discovery of alpha(1a/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 by alpha(1)-adrenergic receptor antagonists. Unfortunately, all currently marketed alpha(1) blockers produced CV related side effects that are caused by the subtype non-selective nature of the drugs. To overcome this problem, it was postulated that a alpha(1a/1d) subtype selective antagonist would bring more benefit for the treatment of BPH/LUTS. In developing selective alpha(1a/1d) ligands, (arylpiperazinyl)cyclohexylsulfonamides were synthesized and their binding profiles against three cloned human alpha(1)-adrenergic receptor subtypes were evaluated. Many compounds show equal affinity for both alpha(1a) and alpha(1d) subtypes with good selectivity against the alpha(1b) subtype. They also overcome the problem of dopamine receptor affinity that previous analogues had exhibited.
Chiu
George
G
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
Li
Shengjian
S
Connolly
Peter J
PJ
Pulito
Virginia
V
Liu
Jingchun
J
Middleton
Steven A
SA
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D003001:Cloning, Molecular; D006801:Humans; D008024:Ligands; D008297:Male; D008956:Models, Chemical; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000473:pathology; D018340:Receptors, Adrenergic, alpha-1; D011954:Receptors, Dopamine / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*; D014570:Urologic Diseases / Q000188:drug therapy* / Q000473:pathology
C547713:ADRA1A protein, human; C547719:ADRA1D protein, human; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1; D011954:Receptors, Dopamine; D013449:Sulfonamides