Design, synthesis and evaluation of 2-aryl benzoxazoles as promising hit for the A<sub>2A</sub> receptor

<p>The development of adenosine A<sub>2A</sub> 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<sub>2A</sub>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<sub>2A</sub> receptor. Compound <b>F1</b>, 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 <b>D1</b> (<i>K<sub>i</sub></i> = 10 μm), can be easily modulated and thus considered as relevant starting points for further hit-to-lead optimisation.</p>