β3-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 β3-adrenoceptor (AR) agonists relaxing the bladder for treatment of urinary dysfunction, 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenoxy]-2-methylpropionic acids (1a–e), into which a fibrate-like structure had been incorporated, were synthesised. Compound 1a was found to be a selective β3-AR agonist in functional assays using the ferret detrusor (β3-AR), rat uterus (β2-AR), and rat atrium (β1-AR); β3: EC50=7.8 nM, β2: IC50=7,300 nM, β1: EC20=23,000 nM. The introduction of a chlorine atom or methyl substituent at the ortho-position on the phenyl ring of 1a further improved β3-AR selectivity. In an in vivo study, 1a lowered intrabladder pressure (ED50=31 μg/kg) in rats, without increasing heart rate, in keeping with the in vitro results. Consequently, it is proposed that 1a and its analogues (1b–e), possess β3-AR agonistic activity in the absence of undesirable β1- or β2-AR mediated actions, and may be useful for clinical treatment and pharmacological studies.