2. Academic Validation
  3. Discovery of an Orally Bioavailable Pan αv Integrin Inhibitor for Idiopathic Pulmonary Fibrosis

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

  • J Med Chem. 2019 Oct 10;62(19):8796-8808. doi: 10.1021/acs.jmedchem.9b00962.
Niall A Anderson 1,  Sebastien Campos 1,  Sharon Butler 1,  Royston C B Copley 1,  Ian Duncan 1,  Stephen Harrison 1,  Joelle Le 1,  Rosemary Maghames 1,  Aleix Pastor-Garcia 1,  John M Pritchard 1,  James E Rowedder 1,  Claire E Smith 1,  Jack Thomas 1,  Giovanni Vitulli 1,  Simon J F Macdonald 1
Affiliations

Affiliation

  • 1 GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.
PMID: 31497959 DOI: 10.1021/acs.jmedchem.9b00962
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%).

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