Article
作者: Jennings, Andy ; Hernandez-Torres, Gloria ; Manam, Padma ; Zou, Hua ; Ermolieff, Jacques ; Qin, Ling ; Balakrishna, Deepika ; DeMent, Kevin ; Proffitt, Chris ; Xu, Rui ; Johnson, Lucas K ; Gibson, Tony S ; Fullenwider, Cody ; Bigi-Botterill, Simone V ; Manohar, Rohan ; Santos, Cipriano ; Dougan, Douglas R ; de Jong, Ron ; Wang, Haixia ; Lindsey, Erick A ; Chen, Chien-Hung ; Ivetac, Tony ; Flick, Andrew C ; Johns, Deidre ; Kwok, Lily ; Sabat, Mark ; Carney, Daniel W ; Vu, Phong ; Miura, Joanne ; Selimkhanov, Jangir ; Chambers, Alison
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.