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

Medicinal Chemistry


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.


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;


  • 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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