Design, synthesis and biological evaluation of nonpeptide integrin antagonists Original Research Article

Recent studies demonstrated that peptide and antibody antagonists of integrin αvβ3 block angiogenesis and tumor growth. In this article, the design, synthesis and biological evaluation of a series of nitroaryl ether-based, nonpeptide mimetics are described. The design of these compounds was based on Merck’s arylether/α-aminoacid/guanidine framework and incorporates a novel nitroaryl system. The synthesized mimetics were tested against a variety of integrins (αvβ3, αIIbβ3, and αvβ5) in order to determine their binding selectivity and ability to inhibit cell adhesion. Selected compounds were also tested for their ability to inhibit angiogenesis in vivo in the CAM (chick chorioallantoic membrane) assay. From the generated compound library, compounds 16 and 19 proved to be potent and selective inhibitors of αIIbβ3 (IC50=14 nM) whereas compound 11 showed excellent in vivo inhibition of angiogenesis (at 30 μg/embryo).