Discovery of +(2-{4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]phenyl}-cyclopropyl)acetic acid as potent and selective αvβ3 inhibitor: Design, synthesis, and optimization

The integrin αvβ3 is expressed in a number of cell types and is thought to play a major role in several pathological conditions. Various small molecules that inhibit the integrin have been shown to suppress tumor growth and retinal angiogenesis. The tripeptide Arg-Gly-Asp (RGD), a common binding motif in several ligands that bind to αvβ3, has been depeptidized and optimized in our efforts toward discovering a small molecule inhibitor. We recently disclosed the synthesis and biological activity of several small molecules that did not contain any peptide bond and mimic the tripeptide RGD. The phenethyl group in one of the lead compounds was successfully replaced with a cyclopropyl moiety. The new lead compound was optimized for potency, selectivity, and for its ADME properties. We describe herein the discovery, synthesis, and optimization of cyclopropyl containing analogs that are potent and selective inhibitors of αvβ3.

The tripeptide RGD a common binding motif in several ligands that bind to αvβ3, has been depeptidized and optimized in our efforts toward discovering a small molecule inhibitor. The cyclopropyl containing new lead compound was optimized for potency, selectivity, and for its ADME properties.Figure optionsDownload as PowerPoint slide