Download MendeleyDesign and Discovery of a Potent and Selective Inhibitor of Integrin alpha v beta 1.
Sabat, M., Carney, D.W., Hernandez-Torres, G., Gibson, T.S., Balakrishna, D., Zou, H., Xu, R., Chen, C.H., de Jong, R., Dougan, D.R., Qin, L., Bigi-Botterill, S.V., Chambers, A., Miura, J., Johnson, L.K., Ermolieff, J., Johns, D., Selimkhanov, J., Kwok, L., DeMent, K., Proffitt, C., Vu, P., Lindsey, E.A., Ivetac, T., Jennings, A., Wang, H., Manam, P., Santos, C., Fullenwider, C., Manohar, R., Flick, A.C.(2024) J Med Chem 67: 10306-10320
- PubMed: 38872300
- DOI: https://doi.org/10.1021/acs.jmedchem.4c00743
- Primary Citation of Related Structures:
8W30 - PubMed Abstract:
Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvβ1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvβ1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvβ1 inhibition.
Organizational Affiliation:
Gastroenterology Drug Discovery Unit, Takeda Development Center Americas, Inc., 9625 Towne Centre Dr., San Diego, California 92121 United States.
