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

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 2; pp. 352 - 355
• Main Authors: Letourneau, Jeffrey J., Liu, Jinqi, Ohlmeyer, Michael H.J., Riviello, Chris, Rong, Yajing, Li, Hong, Appell, Kenneth C., Bansal, Shalini, Jacob, Biji, Wong, Angela, Webb, Maria L.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 15.01.2009
• Subjects: Inhibitors; Integrin; Integrin; Inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.11.074

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.