1. Design and Discovery of a Potent and Selective Inhibitor of Integrin αvβ1.
- Author
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Sabat M, Carney DW, Hernandez-Torres G, Gibson TS, Balakrishna D, Zou H, Xu R, Chen CH, de Jong R, Dougan DR, Qin L, Bigi-Botterill SV, Chambers A, Miura J, Johnson LK, Ermolieff J, Johns D, Selimkhanov J, Kwok L, DeMent K, Proffitt C, Vu P, Lindsey EA, Ivetac T, Jennings A, Wang H, Manam P, Santos C, Fullenwider C, Manohar R, and Flick AC
- Subjects
- Animals, Rats, Humans, Structure-Activity Relationship, Liver Cirrhosis drug therapy, Models, Molecular, Drug Discovery, Rats, Sprague-Dawley, Male, Crystallography, X-Ray, Benzimidazoles pharmacology, Benzimidazoles chemistry, Benzimidazoles chemical synthesis, Drug Design, Receptors, Vitronectin antagonists & inhibitors, Receptors, Vitronectin metabolism
- 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.
- Published
- 2024
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