Synthesis and initial evaluation of novel, non-peptidic antagonists of the α v-integrins α vβ 3 and α vβ 5

Abstract

The discovery, synthesis and preliminary SAR of a novel class of non-peptidic antagonists of the α v-integrins α vβ 3 and α vβ 5 is described. High-throughput screening of an extensive series of ECLiPS™ compound libraries led to the identification of compound 1 as a dual inhibitor of the α v-integrins α vβ 3 and α vβ 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 α vβ 3 and α vβ 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.