Discovery of Novel<i>N</i>-Phenylglycine Derivatives as Potent and Selective β₃-Adrenoceptor Agonists for the Treatment of Frequent Urination and Urinary Incontinence

Abstract

With a novel assay using isolated ferret detrusor to estimate β3-adrenoceptor agonistic activity, we found that a series of glycine derivatives of ritodrine, a β2-adrenoceptor agonist, are potent β3-adrenoceptor agonists, with excellent selectivity versus β1 and β2 subtypes. Substitution of halogens in the phenyl ring increased potency and selectivity for the β3-adrenoceptor, and this was dependent upon the position of the halogens. The chlorine-substituted derivatives 3f−i exhibited potent β3-adrenoceptor-mediated relaxation of ferret detrusor (EC50 = 0.93, 11, 14, and 160 nM) and higher potency at β3-adrenoceptors than at β1 or β2. The intravenous administration of 3h significantly reduced the urinary bladder pressure in anesthetized male rats (ED50 = 48 μg/kg) without cardiovascular side effects. This article is the first report of structure−activity relationships (SAR) concerning β3-adrenoceptor agonists as agents for the treatment of urinary frequency and incontinence.