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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Johan Evenäs
  • Fredrik Edfeldt
  • Matti Lepistö
  • Naila Svitacheva
  • Anna Synnergren
  • Britta Lundquist
  • Mia Gränse
  • Anna Rönnholm
  • Mikael Varga
  • John Wright
  • Min Wei
  • Sherrie Yue
  • Junfeng Wang
  • Chong Li
  • Xuan Li
  • Gang Chen
  • Yong Liao
  • Gang Lv
  • Ann Tjörnebo
  • Frank Narjes
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area
Original languageEnglish
Pages (from-to)1315-1321
JournalBioorganic & Medicinal Chemistry Letters
Volume24
Issue number5
Publication statusPublished - 2014
Publication categoryResearch
Peer-reviewedYes