Lipoyl compounds and methods for treating ischemic injury
Inventors
Baguisi, Alexander B. • Beeuwkes, Reinier • Casale, Ralph • Kates, Steven A. • Lader, Alan S.
Assignees
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Publication Number
US-9359325-B2
Publication Date
2016-06-07
Expiration Date
Abstract
The present invention relates, in various embodiments, to a compound represented by Structural Formula (I), pharmaceutically acceptable salts or prodrugs thereof, and compositions comprising said compounds, or pharmaceutically acceptable salts or prodrugs thereof. Methods of using compounds of Structural Formulas (I) and (Ia) or compositions comprising compounds of Structural Formulas (I) and (Ia), or pharmaceutically acceptable salts or prodrugs thereof, to treat ischemia or ischemia-reperfusion injury are also disclosed.
Core Innovation
The invention relates to lipoyl-based compounds represented by structural formulae (I) and (Ia), including a substituent R and R′ and a definition of X as absent or an amino acid forming an amide linkage. The compounds include stereochemical requirements, including that (R)-lipoyl and (S)-lipoyl stereoisomers are substantially separated based on enantiomeric excess, and the disclosure concerns a series of lipoyl-conjugated amino-acid/acid derivatives and related named derivatives.
The disclosure provides lipoyl-conjugated amino-acid/acid derivatives designated as W–AE and related variants, including RLip-γ-aminobutyric acid, RLip-Phospho-Ser-OH, RLip-β-Fluoro-Ala-OH, RLip-DGlu-OH, SLip/SLip-e-OH variants, N-(RLip)-4-carboxyphenylalanine, N-(RLip)-3-aminobenzenesulfonic acid, N-(RLip)-sulfanilic-OH, RLip-cysteic acid, RLip-2-aminoethyl hydrogen sulfate, RLip-phosphoryl-ethanolamine, RLip-aminoethyl-phosphonic acid, RLip-PABA, and related conjugates.
The invention relates to a pharmaceutical composition comprising a compound represented by a structural formula, or a pharmaceutically acceptable salt thereof, wherein the enantiomeric excess of the compound or pharmaceutically acceptable salt is at least or about 90%, and a pharmaceutically acceptable carrier or diluent. The problem addressed is injury associated with ischemia and ischemia-reperfusion injury, including myocardial infarct size and renal ischemia-reperfusion injury outcomes.
Claims Coverage
The independent claim specifies a pharmaceutical composition containing a compound, or a pharmaceutically acceptable salt, with an enantiomeric excess of at least or about 90%, together with a pharmaceutically acceptable carrier or diluent. Dependent claims refine the enantiomeric excess threshold and add oral administration, tablet or capsule dosage forms, and ex vivo inhibition of ischemia or ischemia-reperfusion injury.
Enantiomeric excess-controlled compound in a carrier composition
A composition comprising a compound represented by a structural formula or a pharmaceutically acceptable salt thereof, wherein the enantiomeric excess of the compound or pharmaceutically acceptable salt is at least or about 90%, and a pharmaceutically acceptable carrier or diluent.
High enantiomeric excess refinement to 95%
The composition further specifies that the enantiomeric excess of the compound or pharmaceutically acceptable salt is at least or about 95%.
Very high enantiomeric excess refinement to 99%
The composition further specifies that the enantiomeric excess of the compound or pharmaceutically acceptable salt is at least or about 99%.
Oral administration adaptation
The composition is adapted to be administered orally.
Tablet or capsule dosage form
The composition is provided in the form of a tablet or capsule.
Ex vivo inhibition of ischemia or ischemia-reperfusion injury by contacting prior to therapy
A method is claimed for inhibiting ischemia or ischemia-reperfusion injury in a cell, tissue, or organ ex vivo by contacting it, prior to therapy, with an effective amount of the composition.
Overall, the claims center on an enantiomerically enriched lipoyl-based compound or salt with enantiomeric excess thresholds of at least or about 90%, 95%, or 99%, formulated with a pharmaceutically acceptable carrier or diluent, with dependent refinements for oral administration and tablet or capsule forms and a method use directed to ex vivo inhibition of ischemia or ischemia-reperfusion injury by pre-therapy contacting.
Stated Advantages
Reduced myocardial infarct size after selected compounds given IV.
Reduced serum creatinine in a partial aortic clamping rat model of renal ischemia-reperfusion injury.
Inhibits ischemia or ischemia-reperfusion injury.
Treating ischemic injury and ischemia-reperfusion injury in a subject.
Inhibiting cell death in vivo.
Inhibiting apoptotic cell death in vivo and in excised tissues or organs ex vivo.
Enabling inhibition of ischemia or ischemia-reperfusion injury in a cell, tissue, or organ ex vivo by pre-therapy contacting.
Documented Applications
In vivo evaluation in which selected compounds given IV reduced myocardial infarct size.
Use in a partial aortic clamping rat model of renal ischemia-reperfusion injury, where certain R-lipoyl compounds reduced serum creatinine.
Ex vivo inhibition of ischemia or ischemia-reperfusion injury in a cell, tissue, or organ by contacting it prior to a therapeutic intervention with an effective amount of the composition.
An in vivo rat MI/AR (myocardial ischemia/reperfusion) efficacy evaluation using an MI/AR ratio readout and myocardial infarct reduction percentages for Table 1 RLip conjugates.
Treating ischemic injury in a subject.
Treating ischemia-reperfusion injury in a subject.
Inhibiting cell death in vivo.
Inhibiting apoptotic cell death in vivo and in excised tissues, organs, or other biological material ex vivo, including pre-therapy contacting.
A method for inhibiting ischemia or ischemia-reperfusion injury in a cell, tissue, or organ ex vivo by contacting prior to therapy with an effective amount of the composition.
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