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Bioorg Med Chem Lett. 2014 Mar 1;24(5):1315-21. doi: 10.1016/j.bmcl.2014.01.050. Epub 2014 Jan 28.

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

Author information

1
AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden. Electronic address: johan.evenas@redglead.com.
2
Discovery Science, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
3
Department of Medicinal Chemistry, Respiratory Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
4
AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
5
Department of Medicinal Chemistry, DMPK and Biology, BioDuro, Life Science Park Road Bld 2, Beijing 102206, PR China.
6
Department of Medicinal Chemistry, Respiratory Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: Frank.Narjes@astrazeneca.com.

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.

KEYWORDS:

High-throughput screening; Hit-to-lead; Non-purine XO inhibitors; Pyrimidone; Xanthine oxidase

PMID:
24508129
DOI:
10.1016/j.bmcl.2014.01.050
[Indexed for MEDLINE]

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