title: Synthesis and initial evaluation of novel, non-peptidic antagonists of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5).
abstract: 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.
authors.affiliation: Department of Chemistry, Pharmacopeia, Inc., PO Box 5350, Princeton, NJ 08543, USA. jletourn@pcop.com
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Letourneau
authors.forename: Jinqi
authors.initials: J
authors.lastname: Liu
authors.forename: Michael H J
authors.initials: MH
authors.lastname: Ohlmeyer
authors.forename: Chris
authors.initials: C
authors.lastname: Riviello
authors.forename: Yajing
authors.initials: Y
authors.lastname: Rong
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Appell
authors.forename: Shalini
authors.initials: S
authors.lastname: Bansal
authors.forename: Biji
authors.initials: B
authors.lastname: Jacob
authors.forename: Angela
authors.initials: A
authors.lastname: Wong
authors.forename: Maria L
authors.initials: ML
authors.lastname: Webb
mesh_terms: 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
chemical_list: D039302:Integrin alphaVbeta3; D047028:Macrocyclic Compounds; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5