Design, synthesis, and evaluation of conformationally restricted acetanilides as potent and selective β3 adrenergic receptor agonists for the treatment of overactive bladder

Article abstract of DOI:10.1021/jm4017224

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.