Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A2A Receptor Antagonists and Their Biological Evaluation

Our initial structure–activity relationship studies on 7-methoxy-4- morpholino- benzothiazolederivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound 25 as a potent and selective A2A adenosine receptor(A2AAdoR) antagonist with reasonable ADMEand pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailabilitymade this series unsuitable for further development. Further optimization using structure-based drug designapproach resulted in discovery of potent and selective adenosine A2A receptorantagonists bearing substituted 1-methylcyclohexyl- carboxamidegroups at position 2 of the benzothiazolescaffold and endowed with better solubility and oral bioavailability. Compounds 41 and 49 demonstrated a number of positive attributes with respect to in vitro ADMEproperties. Both compounds displayed good pharmacokinetic properties with 63% and 61% oral bioavailability, respectively, in rat. Further, compound 49 displa...