Discovery of potent and selective inhibitors of human platelet-type 12- lipoxygenase.

Medicinal Chemistry

Abstract

We report the discovery of novel small molecule inhibitors of platelet-type 12-human lipoxygenase, which display nanomolar activity against the purified enzyme, using a quantitative high-throughput screen (qHTS) on a library of 153607 compounds. These compounds also exhibit excellent specificity, >50-fold selectivity vs the paralogues, 5-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity vs ovine cyclooxygenase-1 and human cyclooxygenase-2. Kinetic experiments indicate this chemotype is a noncompetitive inhibitor that does not reduce the active site iron. Moreover, chiral HPLC separation of two of the racemic lead molecules revealed a strong preference for the (-)-enantiomers (IC(50) of 0.43 ± 0.04 and 0.38 ± 0.05 μM) compared to the (+)-enantiomers (IC(50) of >25 μM for both), indicating a fine degree of selectivity in the active site due to chiral geometry. In addition, these compounds demonstrate efficacy in cellular models, which underscores their relevance to disease modification.

Authors

Kenyon, Victor; Rai Bantukallu, Ganesha; Jadhav, Ajit; Schultz, Lena; Armstrong, Michelle; Jameson, J Brian; Perry, Steven; Joshi, Netra; Bougie, James M; Leister, William; Taylor-Fishwick, David A; Nadler, Jerry L; Holinstat, Michael; Simeonov, Anton; Maloney, David J; Holman, Theodore R;

Keywords

  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid/ antagonists & inhibitors
  • Animals
  • Arachidonate 12-Lipoxygenase/ drug effects
  • Blood Platelets/ enzymology
  • Humans
  • Islets of Langerhans/ drug effects
  • Kinetics
  • Lipoxygenase Inhibitors/ chemical synthesis
  • Lipoxygenase Inhibitors/ pharmacokinetics
  • Lipoxygenase Inhibitors/ pharmacology
  • Mice
  • Sheep
  • Stereoisomerism
  • Structure-Activity Relationship

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