Design, synthesis and biological evaluation of nonpeptide integrin antagonists.
Recent studies demonstrated that peptide and antibody antagonists of integrin alpha v beta 3 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/alpha-aminoacid/guanidine framework and incorporates a novel nitroaryl system. The synthesized mimetics were tested against a variety of integrins (alpha v beta 3, alpha IIb beta 3, and alpha v beta 5) 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 alpha IIb beta 3 (IC50 = 14 nM) whereas compound 11 showed excellent in vivo inhibition of angiogenesis (at 30 micrograms/embryo).
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
K C
KC
Nicolaou
J I
JI
Trujillo
B
B
Jandeleit
K
K
Chibale
M
M
Rosenfeld
B
B
Diefenbach
D A
DA
Cheresh
S L
SL
Goodman
D000482:Allantois / Q000098:blood supply; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D015195:Drug Design; D006801:Humans; D008024:Ligands; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009596:Nitrophenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008024:Ligands; D009596:Nitrophenols; D019030:Receptors, Vitronectin; D013449:Sulfonamides; C116210:nitroaryl ether solfonamide