Discovery of benzothiazole-based adenosine A₂B receptor antagonists with improved A₂A selectivity

The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A₂B antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A₂A and A₁ receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A₂A and A₁ receptors.