438575-88-3Relevant academic research and scientific papers
Discovery of potent and selective inhibitors of human platelet-type 12-lipoxygenase
Kenyon, Victor,Rai, 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.
experimental part, p. 5485 - 5497 (2011/10/09)
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 μM) compared to the (+)-enantiomers (IC50 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.
INHIBITORS OF HUMAN 12-LIPOXYGENASE
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Page/Page column 21-22, (2011/12/04)
Disclosed are inhibitors of human 12-lipoxygenase of Formula (I) or (II), wherein R1, R2, R3, and R4 are as defined herein, that are useful in treating or preventing a 12-lipoxygenase mediated disease or disorder, e.g., diabetes. Also disclosed are a composition comprising a pharmaceutically acceptable carrier and at least one inhibitor of the invention, and a method of treating or preventing such disease or disorder in a mammal.
