Discovery of Potent and Selective Inhibitors of Human Platelet-Type 12-Lipoxygenase

作者：Kenyon Victor; Rai Ganesha; Jadhav Ajit; Schultz Lena; Armstrong Michelle; Jameson J Brian II; 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

来源：Journal of Medicinal Chemistry, 2011, 54(15): 5485-5497.

DOI：10.1021/jm2005089

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 (IC50 of 0.43 +/- 0.04 and 0.38 +/- 0.05 mu M) compared to the (+)-enantiomers (IC50 of >25 mu M 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.

• 出版日期2011-8-11