Abstract
β-Adrenoceptors (β-ARs) are classified into three types; β1-, β2-, and β3-ARs. In humans, the detrusor muscle has recently been reported to be the predominant site of β3-AR mRNA expression. The relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through β3-AR activation, suggesting that β3-adrenergic receptor agonists may represent as potential drugs for treating overactive bladder (OAB). In this paper, we described that the synthesis and discovery of novel class of biphenyl analogues containing an carboxylic acid moiety and acylsulfonamide, which has been identified highly potent and selective human β3-AR agonists with good oral bioavailability. We also described scalable process for our clinical candidate of FK4664 and AS1714955. Furthermore, in a metabolism study of benzoic acid analogues conducted in human hepatocytes, we identified an acylglucuronide conjugated metabolite (M-2), and the M-2 metabolite of FK4664 was prepared with high selectivity.
