HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase.

The identification of novel, non-purine based inhibitors of xanthine oxidase is described. After a high-throughput screening campaign, an NMR based counterscreen was used to distinguish actives, which interact with XO in a reversible manner, from assay artefacts. This approach identified pyrimidone 1 as a reversible and competitive inhibitor with good lead-like properties. A hit to lead campaign gave compound 41, a nanomolar inhibitor of hXO with efficacy in the hyperuricemic rat model after oral dosing.