title: Discovery of potent and selective inhibitors of human platelet-type 12- lipoxygenase.
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: NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-3370, United States.
authors: Victor
authors: V
authors: Kenyon
authors: Ganesha
authors: G
authors: Rai
authors: Ajit
authors: A
authors: Jadhav
authors: Lena
authors: L
authors: Schultz
authors: Michelle
authors: M
authors: Armstrong
authors: J Brian
authors: JB
authors: Jameson
authors: Steven
authors: S
authors: Perry
authors: Netra
authors: N
authors: Joshi
authors: James M
authors: JM
authors: Bougie
authors: William
authors: W
authors: Leister
authors: David A
authors: DA
authors: Taylor-Fishwick
authors: Jerry L
authors: JL
authors: Nadler
authors: Michael
authors: M
authors: Holinstat
authors: Anton
authors: A
authors: Simeonov
authors: David J
authors: DJ
authors: Maloney
authors: Theodore R
authors: TR
authors: Holman
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000037:antagonists & inhibitors; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000187:drug effects*; D001792:Blood Platelets / Q000201:enzymology; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects; D007700:Kinetics; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D012756:Sheep; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D016859:Lipoxygenase Inhibitors; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase