Aminocyclohexylsulfonamides: discovery of metabolically stable 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, but these drugs also produce side effects that are related to their subtype non-selective nature. To overcome this limitation, it was hypothesized that an alpha(1a/1d) subtype-selective antagonist would be efficacious while keeping side effects to a minimum. To discover alpha(1a/1d)-selective antagonists and improve metabolic stability of our previously reported compounds, we have designed and synthesized a series of (phenylpiperazinyl)- or (phenylpiperidinyl)-cyclohexylsulfonamides. By incorporating the information obtained from metabolism studies, we were able to discover several compounds that are both alpha(1a/1d) adrenoceptor subtype selective and show increased stability toward human liver microsomal metabolism. The selectivity profile of these compounds provides great improvement over the commercial drug tamsulosin, hence may pave the way to the development of new and efficacious therapeutic agents with reduced side effects.
Chiu
George
G
Johnson & Johnson Pharmaceutical Research and Development L.L.C., PO Box 300, 1000 Route 202 South, Raritan, NJ 08869, USA.
Li
Shengjian
S
Cai
Hong
H
Connolly
Peter J
PJ
Peng
Sean
S
Stauber
Kathe
K
Pulito
Virginia
V
Liu
Jingchun
J
Middleton
Steven A
SA
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D003514:Cyclohexylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D006801:Humans; D008297:Male; D008861:Microsomes / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D011470:Prostatic Hyperplasia / Q000188:drug therapy*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D003514:Cyclohexylamines; D013449:Sulfonamides