Synthesis and initial evaluation of novel, non-peptidic antagonists of the αv-integrins αvβ3 and αvβ5

The discovery, synthesis and preliminary SAR of a novel class of non-peptidic antagonists of the αv-integrins αvβ3 and αvβ5 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 αv-integrins αvβ3 and αvβ5. 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 αvβ3 and αvβ5 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.