Synthesis and initial evaluation of novel, non-peptidic antagonists of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5).
The discovery, synthesis and preliminary SAR of a novel class of non-peptidic antagonists of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5) is described. High-throughput screening of an extensive series of ECLiPStrade mark compound libraries led to the identification of compound 1 as a dual inhibitor of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5). Optimization of compound 1 involving, in part, introduction of two novel constraints led to the discovery of compounds 15a and 15b with reduced PSA and much improved potency for both the alpha(v)beta(3) and alpha(v)beta(5) integrins. Compounds 15a and 15b were shown to have promising activity in functional cellular assays and compound 15a also exhibited a promising Caco-2 permeability profile.
Letourneau
Jeffrey J
JJ
Department of Chemistry, Pharmacopeia, Inc., PO Box 5350, Princeton, NJ 08543, USA. jletourn@pcop.com
Liu
Jinqi
J
Ohlmeyer
Michael H J
MH
Riviello
Chris
C
Rong
Yajing
Y
Li
Hong
H
Appell
Kenneth C
KC
Bansal
Shalini
S
Jacob
Biji
B
Wong
Angela
A
Webb
Maria L
ML
D001682:Biological Availability; D002460:Cell Line; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D047028:Macrocyclic Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D039302:Integrin alphaVbeta3; D047028:Macrocyclic Compounds; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5