Design and Discovery of a Potent and Selective Inhibitor of Integrin αvß1.
J Med Chem
; 67(12): 10306-10320, 2024 Jun 27.
Article
in En
| MEDLINE
| ID: mdl-38872300
ABSTRACT
Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 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 αvß1 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 αvß1 inhibition.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug Design
/
Receptors, Vitronectin
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
J Med Chem
/
J. med. chem
/
Journal of medicinal chemistry
Year:
2024
Document type:
Article