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J Med Chem. 2019 Sep 9. doi: 10.1021/acs.jmedchem.9b00962. [Epub ahead of print]

The discovery of an orally bioavailable pan-αv integrin inhibitor for idiopathic pulmonary fibrosis.

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 to 40 nM for the integrin receptors named above) possessing excellent oral pharmacokinetic properties in rats (with of clearance 7.6 mL/min/kg and bioavailability 97%).

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