Beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl)phenoxy]-2-methylpropionic acid.
In a search for novel analogues of beta(3)-adrenoceptor (AR) agonists relaxing the bladder for treatment of urinary dysfunction, 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl)phenoxy]-2-methylpropionic acids (1a-e), into which a fibrate-like structure had been incorporated, were synthesised. Compound 1a was found to be a selective beta(3)-AR agonist in functional assays using the ferret detrusor (beta(3)-AR), rat uterus (beta(2)-AR), and rat atrium (beta(1)-AR); beta(3): EC(50)=7.8 nM, beta(2): IC(50)=7,300 nM, beta(1): EC(20)=23,000 nM. The introduction of a chlorine atom or methyl substituent at the ortho-position on the phenyl ring of 1a further improved beta(3)-AR selectivity. In an in vivo study, 1a lowered intrabladder pressure (ED(50)=31 microg/kg) in rats, without increasing heart rate, in keeping with the in vitro results. Consequently, it is proposed that 1a and its analogues (1b-e), possess beta(3)-AR agonistic activity in the absence of undesirable beta(1)- or beta(2)-AR mediated actions, and may be useful for clinical treatment and pharmacological studies.
Tanaka
N
N
Central Research Laboratory, Kissei Pharmaceutical Company Ltd., 4365-1, Hotaka, Nagano, 399-8304, Japan. nobuyuki_tanaka@pharm.kissei.co.jp
Tamai
T
T
Mukaiyama
H
H
Hirabayashi
A
A
Muranaka
H
H
Ishikawa
T
T
Akahane
S
S
Akahane
M
M
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001671:Biochemistry / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005289:Ferrets; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D010636:Phenols; D011422:Propionates / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014549:Urinary Incontinence / Q000188:drug therapy*; D014554:Urination / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects
C449119:2-(4-(2-(((1,2)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)phenoxy)-2-methylpropionic acid; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D010636:Phenols; D011422:Propionates