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 rela xing the bladder for treatment of urinary dysfunction, 2-[4-(2-{[(1S,2R)-2- hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenoxy]-2-methylprop ionic acids (1a-e), into which a fibrate-like structure ha been incorporate d, were synthesised. Compound la was found to be a selective beta (3)-AR ag onist in functional assays using the ferret detrusor (VAR), rat uterus (bet a (2)-AR), and rat atrium (beta (1)-AR): beta (3): EC50 = 7.8 nM, beta (2): IC50 = 7,300 nM, beta (1): EC20 = 23,000 nM. The introduction of a chlorin e atom or methyl substituent at the ortho-position on the phenyl ring of la further improved VAR selectivity. In an in vivo study, la lowered intrabla dder pressure (ED50 = 31 mug/kg) in rats, without increasing heart rate, in keeping with the in vitro results. Consequently, it is proposed that la an d its analogues (1b e), possess beta (3)-AR agonistic activity in the absen ce of undesirable beta (1)- or beta (2)-AR mediated actions. and may be use ful for clinical treatment and pharmacological studies. (C) 2001 Elsevier S cience Ltd. All rights reserved.