title: Potent and selective inhibitors of human reticulocyte 12/15-lipoxygenase as anti-stroke therapies.
abstract: A key challenge facing drug discovery today is variability of the drug target between species, such as with 12/15-lipoxygenase (12/15-LOX), which contributes to ischemic brain injury, but its human and rodent isozymes have different inhibitor specificities. In the current work, we have utilized a quantitative high-throughput (qHTS) screen to identify compound 1 (ML351), a novel chemotype for 12/15-LOX inhibition that has nanomolar potency (IC50 = 200 nM) against human 12/15-LOX and is protective against oxidative glutamate toxicity in mouse neuronal HT22 cells. In addition, it exhibited greater than 250-fold selectivity versus related LOX isozymes, was a mixed inhibitor, and did not reduce the active-site ferric ion. Lastly, 1 significantly reduced infarct size following permanent focal ischemia in a mouse model of ischemic stroke. As such, this represents the first report of a selective inhibitor of human 12/15-LOX with demonstrated in vivo activity in proof-of-concept mouse models of stroke.
authors.affiliation: Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School , Charlestown, Massachusetts 02129, United States.
authors.forename: Ganesha
authors.initials: G
authors.lastname: Rai
authors.forename: Netra
authors.initials: N
authors.lastname: Joshi
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Jung
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Lena
authors.initials: L
authors.lastname: Schultz
authors.forename: Adam
authors.initials: A
authors.lastname: Yasgar
authors.forename: Steve
authors.initials: S
authors.lastname: Perry
authors.forename: Giovanni
authors.initials: G
authors.lastname: Diaz
authors.forename: Qiangli
authors.initials: Q
authors.lastname: Zhang
authors.forename: Victor
authors.initials: V
authors.lastname: Kenyon
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Klaus
authors.initials: K
authors.lastname: van Leyen
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holman
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D012156:Reticulocytes / Q000201:enzymology*; D020521:Stroke / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: C475064:12-15-lipoxygenase; D016859:Lipoxygenase Inhibitors; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase