Compositions and methods for treating ischemia and ischemia-reperfusion injury
Inventors
Baguisi, Alexander • Beeuwkes, Reinier • Casale, Ralph • Kates, Steven A. • Lader, Alan
Assignees
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Publication Number
US-8772249-B2
Publication Date
2014-07-08
Expiration Date
Abstract
The present invention relates to compositions comprising a substantially pure compound represented by Structural Formula I: and methods of using such compounds to activate cytoprotective kinases. The values and preferred values of the variables in Structural Formula I are defined herein.
Core Innovation
The invention relates to lipoyl-containing prodrugs and derivatives defined by Structural Formulas I-III, including substantially pure compounds, ester forms, and pharmaceutically acceptable salt forms. R1 and R2 are each H or a hydrolyzable group, and the hydrolyzable groups are associated with a prodrug concept in which hydrolysis yields carboxylic acids.
The invention further relates to treatment of ischemic injury or ischemia-reperfusion injury by administering an effective amount of the compounds to a subject in need thereof. The disclosure links the structurally defined compounds to activation of cytoprotective kinases, including Akt, insulin receptor kinase (IRK), IGF1R kinase, and Src kinase, and to inhibition of apoptosis in cells, tissues, and organs.
Additional stated effects include reduction of cytosolic calcium associated with ischemia and increase in peroxyl radical absorbance and ORAC capacity to counter reactive oxygen species during reperfusion and ischemia-reperfusion. The therapeutic coverage includes ischemic injury affecting multiple organs and conditions, and selected diabetic conditions.
Claims Coverage
The independent claims cover three inventive features: treatment of ischemic injury or ischemia-reperfusion injury, treatment of selected diabetic conditions, and stereochemical purity constraints on the administered lipoyl-containing compounds or pharmaceutically acceptable salts.
Treating ischemic injury or ischemia-reperfusion injury using hydrolyzable R1/R2 lipoyl-containing compounds with optical purity
A method for treating an ischemic injury or an ischemia-reperfusion injury comprising administering an effective amount of a compound represented by a structural formula or a pharmaceutically acceptable salt thereof wherein R1 and R2 are each independently H or a hydrolyzable group, and wherein the compound has a percent optical purity of at least 90% by weight relative to the other stereoisomers.
Treating ischemic injury or ischemia-reperfusion injury using enantiomerically pure hydrolyzable R1/R2 lipoyl-containing compounds
A method for treating an ischemic injury or an ischemia-reperfusion injury comprising administering an effective amount of a compound represented by a structural formula or a pharmaceutically acceptable salt thereof wherein R1 and R2 are each independently H or a hydrolyzable group, and wherein the compound or pharmaceutically acceptable salt thereof is at least 90% enantiomerically pure.
Treating selected diabetic conditions using hydrolyzable R1/R2 lipoyl-containing compounds with optical purity
A method for treating a diabetic condition in a subject, selected from diabetic neuropathy, diabetic ulcer, diabetic mephropathy, and diabetic retinopathy, comprising administering an effective amount of a compound represented by a structural formula or a pharmaceutically acceptable salt thereof wherein R1 and R2 are each independently H or a hydrolyzable group, and wherein the compound has a percent optical purity of at least 90% by weight relative to the other stereoisomers.
Across the independent claims, the core inventive coverage is the use of lipoyl-containing compounds or derivatives having R1 and R2 each independently H or a hydrolyzable group for treating ischemic injury, ischemia-reperfusion injury, or selected diabetic conditions, with optical purity or enantiomeric purity constraints.
Stated Advantages
Inhibit apoptosis in cells, tissues, and organs.
Reduce ischemia and ischemia-reperfusion injury, including myocardial ischemia-reperfusion injury.
Reduce infarct size/area at risk in the rat myocardial ischemia-reperfusion model.
Decrease cytosolic calcium associated with ischemia.
Increase peroxyl radical absorbance and ORAC capacity to counter reactive oxygen species during reperfusion and ischemia-reperfusion.
Activate cytoprotective kinases, including Akt, insulin receptor kinase, IGF1R kinase, and Src kinase.
Documented Applications
Use for cardioprotection in ischemia and ischemia-reperfusion injury, including myocardial ischemia-reperfusion injury.
Activation of cytoprotective kinases in the context of inhibiting apoptosis and improving ischemic outcomes.
Treatment of ischemic injury or ischemia-reperfusion injury in a subject in need thereof, including cardiac, cerebral, renal, hepatic, and other ischemia-related targets.
Treatment of diabetic conditions selected from diabetic neuropathy, diabetic ulcer, diabetic mephropathy, and diabetic retinopathy.
Treatment of ischemia-reperfusion cardiomyopathy and peri-operative cardiac damage.
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