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

摘要: Our initial structure–activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives 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 ADME pharmacokinetic properties. However, poor intrinsic solubility low moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug design approach resulted in discovery antagonists bearing substituted 1-methylcyclohexyl-carboxamide groups position 2 benzothiazole scaffold endowed better bioavailability. Compounds 41 49 demonstrated number positive attributes respect vitro Both compounds displayed good properties 63% 61% bioavailability, respectively, rat. Further, displa...