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Moyes, Christopher R; Berger, Richard; Goble, Stephen D; Harper, Bart; Shen, Dong-Ming; Wang, Liping; Bansal, Alka; Brown, Patricia N; Chen, Airu S; Dingley, Karen H; Di Salvo, Jerry; Fitzmaurice, Aileen; Gichuru, Loise N; Hurley, Amanda L; Jochnowitz, Nina; Miller, Randall R; Mistry, Shruty; Nagabukuro, Hiroshi; Salituro, Gino M; Sanfiz, Anthony; Stevenson, Andra S; Villa, Katherine; Zamlynny, Beata; Struthers, Mary; Weber, Ann E; Edmondson, Scott D
Journal of medicinal chemistry, 02/2014, Letnik: 57, Številka: 4Journal Article
A series of conformationally restricted acetanilides were synthesized and evaluated as β3-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 and 29, 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 dependent β3-AR mediated responses in a rat bladder hyperactivity model.
