Abstract
Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acids / chemistry*
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Amino Acids / pharmacokinetics
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Amino Acids / pharmacology*
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Amino Acids / therapeutic use
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Animals
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Arginase / antagonists & inhibitors*
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Arginase / chemistry
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Boron Compounds / chemistry*
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Boron Compounds / pharmacokinetics
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Boron Compounds / pharmacology*
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Boron Compounds / therapeutic use
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CHO Cells
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Caproates / chemistry*
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Caproates / pharmacokinetics
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Caproates / pharmacology*
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Caproates / therapeutic use
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Cricetinae
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Cricetulus
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Drug Discovery*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Humans
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Male
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Models, Molecular
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Myocardial Reperfusion Injury / drug therapy*
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Protein Conformation
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Rats
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Structure-Activity Relationship
Substances
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2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid
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Amino Acids
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Boron Compounds
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Caproates
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Enzyme Inhibitors
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hexanoic acid
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ARG1 protein, human
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ARG2 protein, human
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Arginase