Benzenesulfonamide indole inhibitors of cytosolic phospholipase A2α: Optimization of in vitro potency and rat pharmacokinetics for oral efficacy

Katherine L. Lee, Mark L. Behnke, Megan A. Foley, Lihren Chen, Weiheng Wang, Richard Vargas, Jill Nunez, Steve Tam, Nevena Mollova, Xin Xu, Marina W.H. Shen, Manjunath K. Ramarao, Debra G. Goodwin, Cheryl L. Nickerson-Nutter, William M. Abraham, Cara Williams, James D. Clark, John C. McKew

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


The synthesis and structure-activity relationship of a series of benzenesulfonamide indole inhibitors of cPLA2α are described. Substitution of the benzenesulfonamide led to analogues with 50-fold improvement in potency versus the unsubstituted benzenesulfonamide lead compound. Rat pharmacokinetics in a minimal formulation was used to prioritize compounds, leading to the discovery of a potent inhibitor of cPLA2α with oral efficacy in models of rat carrageenan paw edema and Ascaris suum airway challenge in naturally sensitized sheep.

Original languageEnglish (US)
Pages (from-to)1345-1358
Number of pages14
JournalBioorganic and Medicinal Chemistry
Issue number3
StatePublished - Feb 1 2008


  • Animal model
  • Asthma
  • Carrageenan paw edema
  • Formulation
  • Inflammation
  • Inhibitor
  • Pharmacokinetics
  • Phospholipase

ASJC Scopus subject areas

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


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