Abstract
A series of caspase inhibitors containing γ-amino acid moiety have been synthesized. A systemic study on their structure-activity relationship of anti-apoptotic cellular activity is presented. These efforts led to the discovery of compound 20o as a potent caspase inhibitor, which demonstrated preclinical ameliorating total bilirubin efficacy with a significantly improved pharmacokinetic profile.
Keywords:
Apoptosis; Caspase inhibitor; Chronic liver disease; γ-Amino acid.
Copyright © 2018. Published by Elsevier Ltd.
MeSH terms
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Amino Acids / chemistry*
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Animals
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Bilirubin / blood
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Binding Sites
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Caspase 1 / chemistry
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Caspase 1 / metabolism
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Caspase Inhibitors / chemistry*
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Caspase Inhibitors / pharmacokinetics
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Caspase Inhibitors / therapeutic use
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Disease Models, Animal
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Half-Life
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Humans
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Jurkat Cells
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Liver Diseases / drug therapy
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Liver Diseases / pathology
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Mice
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Molecular Docking Simulation
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Protein Structure, Tertiary
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Structure-Activity Relationship
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fas Receptor / antagonists & inhibitors
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fas Receptor / metabolism
Substances
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Amino Acids
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Caspase Inhibitors
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FAS protein, human
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fas Receptor
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Caspase 1
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Bilirubin