HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase.
Related Articles HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase.
Bioorg Med Chem Lett. 2014 Mar 1;24(5):1315-21
Authors: Evenäs J, Edfeldt F, Lepistö M, Svitacheva N, Synnergren A, Lundquist B, Gränse M, Rönnholm A, Varga M, Wright J, Wei M, Yue S, Wang J, Li C, Li X, Chen G, Liao Y, Lv G, Tjörnebo A, Narjes F
Abstract
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.
PMID: 24508129 [PubMed - indexed for MEDLINE]
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