Design and Discovery of a Potent and Selective Inhibitor of Integrin αvß1.
J Med Chem
; 67(12): 10306-10320, 2024 Jun 27.
Article
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| 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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
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Receptores de Vitronectina
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2024
Tipo del documento:
Article