Antagonists of the adenosine A 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 A adenosine receptor (AR) antagonists. Two hits were identified with interesting pharmacokinetic properties but were find to bind the hAR receptor in the micromolar-range. Herein, in order to enhance affinity toward the hAR, 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, IC = 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 A antagonists.