Design, Synthesis and Evaluation of Conformationally Restricted Acetanilides as Potent and Selective β3 Adrenergic Receptor Agonists for the Treatment of Overactive Bladder
Moyes CR, Berger R, Goble SD, Harper B, Shen DM, Wang L, Bansal A, Brown PN, Chen AS, Dingley KH, Di Salvo J, Fitzmaurice A, Gichuru LN, Hurley AL, Jochnowitz N, Miller RR, Mistry S, Nagabukuro H, Salituro GM, Sanfiz A, Stevenson AS, Villa K, Zamlynny B, Struthers M, Weber AE, Edmondson SD. J Med Chem. 2014 Jan 17. [Epub ahead of print]

Abstract

A series of conformationally restricted acetanilides were synthesized and evaluated as Beta 3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and29 which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependant β3-AR mediated responses in a rat bladder hyperactivity model.