Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1

Kai Ding, Ziyuan Zhou, Shuo Zhou, Yaxia Yuan, Kyungbo Kim, Ting Zhang, Xirong Zheng, Fang Zheng, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Human mPGES-1 has emerged as a promising target in exploring a next generation of anti-inflammatory drugs, as selective mPGES-1 inhibitors are expected to discriminatively suppress the production of induced PGE2 without blocking the normal biosynthesis of other prostanoids including homeostatic PGE2. Therefore, this therapeutic approach is believed to reduce the adverse effects associated with the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). Identified from structure-based virtue screening, the compound with (Z)-5-benzylidene-2-iminothiazolidin-4-one scaffold was used as lead in rational design of novel inhibitors. Besides, we further designed, synthesized, and evaluated 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and structurally related derivatives for their in vitro inhibitory activities. According to in vitro activity assays, a number of these compounds were capable of inhibiting human mPGES-1, with the desirable selectivity for mPGES-1 over COX isozymes.

Original languageEnglish (US)
Pages (from-to)858-862
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number5
DOIs
StatePublished - Mar 1 2018
Externally publishedYes

Keywords

  • Anti-inflammatory drugs
  • Barbituric acid
  • mPGES-1 inhibitor
  • Pyrazole

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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