Discovery of potent and selective inhibitors of human platelet-type 12- lipoxygenase.
Basic Information
ID: ALA1811753
Journal: J Med Chem
Title: Discovery of potent and selective inhibitors of human platelet-type 12- lipoxygenase.
Authors: Kenyon V, Rai G, Jadhav A, Schultz L, Armstrong M, Jameson JB, Perry S, Joshi N, Bougie JM, Leister W, Taylor-Fishwick DA, Nadler JL, Holinstat M, Simeonov A, Maloney DJ, Holman TR.
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.
CiteXplore: 21739938
DOI: 10.1021/jm2005089
Patent ID: ┄