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)-adre noceptor agonistic activity, we found that a series of glycine derivatives of ritodrine, a beta (2)-adrenoceptor agonist, are potent beta (3)-adrenoce ptor agonists, with excellent selectivity versus beta1 and beta (2) subtype s. Substitution of halogens in the phenyl ring increased potency and select ivity for the beta (3)-adrenoceptor, and this was dependent upon the positi on of the halogens. The chlorine-substituted derivatives 3f-i exhibited pot ent beta (3)-adrenoceptor-mediated relaxation of ferret detrusor (EC50 = 0. 93, 11, 14, and 160 nM) and higher potency at beta (3)-adrenoceptors than a t beta (1) or beta (2) The intravenous administration of 3h significantly r educed the urinary bladder pressure in anesthetized male rats (ED50 = 48 mu g/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 .