Journal : J. Med. Chem.
Title : Discovery of novel N-phenylglycine derivatives as potent and selective beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence.
Year : 2001
Volume : 44
Issue : 9
First Page : 1436
Last Page : 1445
Authors : Tanaka N, Tamai T, Mukaiyama H, Hirabayashi A, Muranaka H, Akahane S, Miyata H, Akahane M.
Abstract : 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.
