Substituted benzocyloheptenes as potent and selective alpha(v) integrin antagonists.
A novel series of potent and specific alpha(v) integrin antagonists has been obtained by aminoalkyl substitutions on benzocyloheptene acetic acids as a rigid GD bioisostere. The preferred compounds 1-2, 1-3 and 1-8, showed nano- to subnanomolar IC(50) values on alpha(v)beta(3) and alpha(v)beta(5) integrins, with favorable pharmacokinetics.
Perron-Sierra
Françoise
F
Institut de Recherches Servier, 125 chemin de Ronde, 78290 Croissy sur Seine, France.
Saint Dizier
Dominique
D
Bertrand
Marc
M
Genton
Annie
A
Tucker
Gordon C
GC
Casara
Patrick
P
D000818:Animals; D001567:Benzocycloheptenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D001682:Biological Availability; D002448:Cell Adhesion / Q000187:drug effects; D002463:Cell Membrane Permeability; D006801:Humans; D020128:Inhibitory Concentration 50; D039564:Integrin alphaV / Q000187:drug effects*; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors; D016023:Integrins / Q000037:antagonists & inhibitors; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D051381:Rats; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D001567:Benzocycloheptenes; D039564:Integrin alphaV; D039302:Integrin alphaVbeta3; D016023:Integrins; D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; C047981:arginyl-glycyl-aspartic acid