Discovery of novel N-phenylglycine derivatives as potent and selective beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence.
With a novel assay using isolated ferret detrusor to estimate beta(3)-adrenoceptor agonistic activity, we found that a series of glycine derivatives of ritodrine, a beta(2)-adrenoceptor agonist, are potent beta(3)-adrenoceptor agonists, with excellent selectivity versus beta(1) and beta(2) subtypes. Substitution of halogens in the phenyl ring increased potency and selectivity for the beta(3)-adrenoceptor, and this was dependent upon the position of the halogens. The chlorine-substituted derivatives 3f-i exhibited potent beta(3)-adrenoceptor-mediated relaxation of ferret detrusor (EC(50) = 0.93, 11, 14, and 160 nM) and higher potency at beta(3)-adrenoceptors than at beta(1) or beta(2). The intravenous administration of 3h significantly reduced the urinary bladder pressure in anesthetized male rats (ED(50) = 48 microg/kg) without cardiovascular side effects. This article is the first report of structure-activity relationships (SAR) concerning beta(3)-adrenoceptor agonists as agents for the treatment of urinary frequency and incontinence.
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
Akahane
S
S
Miyata
H
H
Akahane
M
M
D000318:Adrenergic beta-Agonists / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D005289:Ferrets; D005998:Glycine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D011312:Pressure; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology; D014549:Urinary Incontinence / Q000188:drug therapy; D014554:Urination / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects / Q000502:physiology
D000318:Adrenergic beta-Agonists; C425783:N-(2,6-dichloro-4-(2-((2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)phenyl)aminoacetic acid; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D005998:Glycine