N-Aryl-gamma-lactams as integrin alphavbeta3 antagonists.
Novel alphavbeta3 antagonists based on the N-aryl-gamma-lactam scaffold were prepared. SAR studies led to the identification of potent antagonists for alphavbeta3 receptor with excellent selectivity against the structurally related alpha(IIb)beta3 receptor. Additional interactions of N-aryl-gamma-lactam derivatives with alphavbeta3 were found when compared to c(-RGDf[NMe]V-) peptide antagonist. The effects of the conformation and configuration of the gamma-lactam core on the binding were also assessed.
Xi
Ning
N
Chemistry Research and Discovery, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA.
Arvedson
Stephen
S
Eisenberg
Shawn
S
Han
Nianhe
N
Handley
Michael
M
Huang
Liang
L
Huang
Qi
Q
Kiselyov
Alexander
A
Liu
Qingyian
Q
Lu
Yuelie
Y
Nunez
Gladys
G
Osslund
Timothy
T
Powers
David
D
Tasker
Andrew S
AS
Wang
Ling
L
Xiang
Tingjian
T
Xu
Shimin
S
Zhang
Jiandong
J
Zhu
Jiawang
J
Kendall
Richard
R
Dominguez
Celia
C
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D007769:Lactams / Q000138:chemical synthesis / Q000494:pharmacology*; D008024:Ligands; D008968:Molecular Conformation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000187:drug effects; D013329:Structure-Activity Relationship
D039302:Integrin alphaVbeta3; D007769:Lactams; D008024:Ligands; D019039:Platelet Glycoprotein GPIIb-IIIa Complex