US EPA

1506483 

Journal Article 

Discovery of Novel Selective Human beta(3) Adrenergic Receptor Agonists as Potential Overactive Bladder (OAB) Therapies 

Imanishi, M; Hattori, K 

2011 

1 

Yuki Gosei Kagaku Kyokaishi
ISSN: 0037-9980 

69 

12 

1402-1410 

WOS:000298717400007 

beta-Adrenoceptors (beta-ARs) are classified into three
types; beta(1)-, beta(2)-, and beta(3)-ARs. In humans, the detrusor muscle has recently been
reported to be the predominant site of beta(3)-AR mRNA expression. The relaxation induced by
adrenergic stimulation of the human detrusor is mediated mainly through beta(3)-AR activation,
suggesting that beta(3)-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 beta(3)-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. 

beta(3)-adrenoceptors (beta-AR(3)); overactive bladder; receptor; agonist; biphenyl carboxylic acid; biphenyl acylsulfonamide; FK4664; AS1714955; metabolism; acylglucuronide