Abstract
The heterodimeric transmembrane αv integrin receptors have recently emerged as potential targets for the treatment of idiopathic pulmonary fibrosis. Herein, we describe how subtle modifications of the central aromatic ring of a series of phenylbutyrate-based antagonists of the vitronectin receptors αvβ3 and αvβ5 significantly change the biological activities against αvβ6 and αvβ8. This resulted in the discovery of a pan αv antagonist (compound 39, 4-40 nM for the integrin receptors named above) possessing excellent oral pharmacokinetic properties in rats (with a clearance of 7.6 mL/(min kg) and a bioavailability of 97%).
MeSH terms
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Administration, Oral
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Animals
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Antigens, Neoplasm / metabolism
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Binding Sites
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Crystallography, X-Ray
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Drug Evaluation, Preclinical
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Half-Life
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Humans
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Idiopathic Pulmonary Fibrosis / drug therapy
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Idiopathic Pulmonary Fibrosis / metabolism
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Idiopathic Pulmonary Fibrosis / pathology*
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Integrin alphaV / chemistry*
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Integrin alphaV / metabolism
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Integrin alphaVbeta3 / antagonists & inhibitors
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Integrin alphaVbeta3 / metabolism
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Integrins / antagonists & inhibitors
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Integrins / metabolism
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Molecular Conformation
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Molecular Docking Simulation
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Phenylbutyrates / chemistry*
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Phenylbutyrates / pharmacokinetics
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Phenylbutyrates / therapeutic use
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Protein Structure, Tertiary
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Rats
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Receptors, Vitronectin / antagonists & inhibitors
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Receptors, Vitronectin / metabolism
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Structure-Activity Relationship
Substances
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Antigens, Neoplasm
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Integrin alphaV
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Integrin alphaVbeta3
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Integrins
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Phenylbutyrates
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Receptors, Vitronectin
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integrin alphaVbeta5
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integrin alphavbeta6