Discovery of an Orally Bioavailable Pan αv Integrin Inhibitor for Idiopathic Pulmonary Fibrosis

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%).