Discovery of Cytochrome P450 4F11 Activated Inhibitors of Stearoyl Coenzyme A Desaturase

Sarah E. Winterton, Emanuela Capota, Xiaoyu Wang, Hong Chen, Prema L. Mallipeddi, Noelle S. Williams, Bruce A. Posner, Deepak Nijhawan, Joseph M. Ready

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Stearoyl-CoA desaturase (SCD) catalyzes the first step in the conversion of saturated fatty acids to unsaturated fatty acids. Unsaturated fatty acids are required for membrane integrity and for cell proliferation. For these reasons, inhibitors of SCD represent potential treatments for cancer. However, systemically active SCD inhibitors result in skin toxicity, which presents an obstacle to their development. We recently described a series of oxalic acid diamides that are converted into active SCD inhibitors within a subset of cancers by CYP4F11-mediated metabolism. Herein, we describe the optimization of the oxalic acid diamides and related N-acyl ureas and an analysis of the structure-activity relationships related to metabolic activation and SCD inhibition.

Original languageEnglish (US)
Pages (from-to)5199-5221
Number of pages23
JournalJournal of Medicinal Chemistry
Volume61
Issue number12
DOIs
StatePublished - Jun 28 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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