Inhibitors of human 12/15-lipoxygenase
Inventors
Van Leyen, Klaus Joachin • Holman, Theodore R. • Maloney, David J. • Jadhav, Ajit • Simeonov, Anton • RAI, Ganesha
Assignees
General Hospital Corp • Childrens Hospital Corp • University of California San Diego UCSD • US Department of Health and Human Services
Publication Number
US-10287279-B2
Publication Date
2019-05-14
Expiration Date
2034-08-22
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Abstract
A systematic screening has revealed a family of compounds that exhibit inhibitory effects on 12/15-lipoxygenase. Accordingly, the present invention relates to the use of these compounds for the inhibition of 12/15-lipoxygenase and for the treatment of a condition involving 12/15-lipoxygenase. Exemplary conditions include, but are not limited to, stroke, periventricular leukomalacia, cardiac arrest with resuscitation, atherosclerosis, Parkinson's disease, Alzheimer's disease, and breast cancer.
Core Innovation
The invention relates to compositions and methods for inhibiting human 12/15-lipoxygenase (12/15-LOX) and treating conditions involving 12/15-LOX, using novel inhibitors identified through systematic screening. These inhibitors target both human and mouse 12/15-LOX homologues, addressing issues related to species variability in drug targets. The compounds have the general Formula I and can be pharmaceutically acceptable salts thereof, with specific substituents defined for X, R11, R12, and R13.
The problem being solved involves the challenge of drug target species variability, particularly with 12/15-LOX, which has different inhibitor specificities in humans and rodents. Existing inhibitors often lack selectivity and may have off-target effects due to antioxidant properties. Humanized animal models are generally unavailable, so identifying compounds effective against both human and mouse 12/15-LOX is critical for drug development. The invention addresses this by discovering and optimizing compounds that inhibit 12/15-LOX selectively across species and demonstrate in vivo efficacy, such as reducing infarct size in mouse stroke models.
Claims Coverage
The patent claims include one independent claim that covers methods of treating 12/15-lipoxygenase-related conditions using specified compounds, encompassing their chemical structure and therapeutic use.
Method of treating a condition involving 12/15-lipoxygenase
Administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, where the compound is defined by the structural features X as O or S, R11 as an optionally substituted aryl, heteroaryl, cyclyl, or heterocyclyl, and R12 and R13 independently as optionally substituted hydrogen, halogen, alkyl, alkenyl, alkynyl, aralkyl, acyl, aryl, heteroaryl, cyclyl, or heterocyclyl.
Specific substituents on the compound for improved efficacy
Where R11 is an aryl or heteroaryl, excluding sulfur in the heteroaryl, and phenyl substituents are not alkyl or alkoxy; specifically R11 can be 1-naphthyl, 2-naphthyl, 6-isoquinolinyl, 2,3-dichlorophenyl, or 3,4-dichlorophenyl. R12 and R13 can be hydrogen, alkyl (methyl to pentyl), aralkyl, acyl, aryl, or heterocyclyl, with particular preference for R12 as hydrogen and R13 as hydrogen, methyl, ethyl, propyl, butyl, pentyl, or phenyl.
Use of specific compound forms
Using compounds of Formula I as defined, or forms corresponding to Formula II with X as O or S and R11 as substituted aryl or heteroaryl, or Formula III with R12 and R13 as defined. Included are specific compounds such as 5-(methylamino)-2-naphthalen-1-yl-1,3-oxazole-4-carbonitrile (ML351) and related dichlorophenyl and thiazole analogs.
Treatment of specific conditions
The method is applicable to treating conditions including stroke, periventricular leukomalacia, cardiac arrest with resuscitation, atherosclerosis, Parkinson's disease, Alzheimer's disease, and breast cancer.
The claims predominantly cover the therapeutic use of specified compounds with defined structural features as 12/15-lipoxygenase inhibitors for treatment of various diseases involving 12/15-LOX, highlighting selectivity and dual-species activity.
Stated Advantages
Compound 1 (ML351) exhibits nanomolar potency and high selectivity for human 12/15-LOX versus related lipoxygenases and cyclooxygenases.
ML351 shows efficacy in protecting mouse neuronal cells from oxidative glutamate toxicity and significantly reduces infarct size in a mouse model of ischemic stroke.
The compound demonstrates favorable in vitro ADME properties, including stability in plasma and buffers, brain penetration, and acceptable pharmacokinetics suitable for in vivo use.
ML351 reduces hemorrhagic transformation in warfarin-pretreated mice after experimental stroke, indicating potential use in patients on oral anticoagulants and compatibility with tPA treatment.
Documented Applications
Treatment of stroke, including ischemic stroke and hemorrhagic transformation following stroke.
Treatment of periventricular leukomalacia, cardiac arrest with resuscitation, atherosclerosis, Parkinson's disease, Alzheimer's disease, and breast cancer.
Use as a pharmacological agent to inhibit 12/15-lipoxygenase in humans and mammals.
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