Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues: Inhibition of inosine monophosphate dehydrogenase

Liqiang Chen, Riccardo Petrelli, Magdalena Olesiak, Daniel J. Wilson, Nicholas P. Labello, Krzysztof W. Pankiewicz

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Synthesis of novel inhibitors of human IMP dehydrogenase is described. These inhibitors are isosteric methylenebis(sulfonamide) analogues 5-8 of earlier reported mycophenolic adenine methylenebis(phosphonate)s 1-3. The parent bis(phosphonate) 1 and its bis(sulfonamide) analogue 5 showed similar sub-micromolar inhibitory activity against IMPDH2 (Ki ∼ 0.2 μM). However, the bis(sulfonamide) analogues 6 and 8 substituted at the position 2 of adenine were approximately 3- to 10-fold less potent inhibitors of IMPDH2 (Ki = 0.3-0.4 μM) than the corresponding parent bis(phosphonate)s 2 and 3 (Ki = 0.04-0.11μM), respectively.

Original languageEnglish (US)
Pages (from-to)7462-7469
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number15
DOIs
StatePublished - Aug 1 2008

Keywords

  • Inosine monophosphate dehydrogenase
  • Methylenebis(phoshonate)
  • Methylenebis(sulfonamide)
  • Mycophenolic acid
  • NAD analogues
  • Nicotinamide adenine dinucleotide

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