Design, synthesis and evaluation of 2-aryl benzoxazoles as promising hit for the A(2A) receptor

The development of adenosine A(2A) receptor antagonists has received much interest in recent years for the treatment of neurodegenerative diseases. Based on docking studies, a new series of 2-arylbenzoxazoles has been identified as potential A(2A)R antagonists. Structure-affinity relationship was investigated in position 2, 5 and 6 of the benzoxazole heterocycle leading to compounds with a micromolar affinity towards the A(2A) receptor. Compound F1, with an affinity of 1 μm, presented good absorption, distribution, metabolism and excretion properties with an excellent aqueous solubility (184 μm) without being cytotoxic at 100 μm. This compound, along with low-molecular weight compound D1 (K(i) = 10 μm), can be easily modulated and thus considered as relevant starting points for further hit-to-lead optimisation.