Antagonists of the adenosine A2A receptor based on a 2-arylbenzoxazole scaffold: Investigation of the C5- and C7-positions to enhance affinity

We have recently reported a series of 2-furoyl-benzoxazoles as potential A2A adenosine receptor (A2AR) antagonists. Two hits were identified with interesting pharmacokinetic properties but were find to bind the hA2AR receptor in the micromolar-range. Herein, in order to enhance affinity toward the hA2AR, we explored the C5- and C7-position of hits 1 and 2 based on docking studies. These modifications led to compounds with nanomolar-range affinity (e.g. 6a, Ki = 40 nM) and high antagonist activity (e.g. 6a, IC50 = 70.6 nM). Selected compounds also exhibited interesting in vitro DMPK (Drug Metabolism and Pharmacokinetics) properties including high solubility and low cytotoxicity. Therefore, the benzoxazole ring appears as a highly effective scaffold for the design of new A2A antagonists. [Display omitted] •Introduction of furan at C7 position of 2-arylbenzoxazole greatly improved A2A affinity.•Affinity and functional data reported at hA2A adenosine receptor.•Through an in silico recepto-driven appoach, ligands affinity was improved.•Identification of new benzoxazole ligands with good functional antagonist potency and DMPK properties.