GW-6604, an ALK5 inhibitor, exhibits clear antifibrotic effects leading to improved liver function.

GW-6604 inhibited autophosphorylation of ALK5 with an IC50 of 140 nM and in a cellular assay inhibited TGF-beta-induced transcription of PAI-1 (IC50 = 500 nM)[2].

GW-6604 (40 mg/kg p.o.) increased liver regeneration in TGF-beta-overexpressing mice, which had undergone partial hepatectomy. In an acute model of liver disease, GW-6604 reduced by 80% the expression of collagen IA1. In a chronic model of DMN-induced fibrosis where DMN was administered for 6 weeks and GW-6604 dosed for the last 3 weeks (80 mg/kg p.o., b.i.d.), mortality was prevented and DMN-induced elevations of mRNA encoding for collagen IA1, IA2, III, TIMP-1 and TGF-beta were reduced by 50-75%. Inhibition of matrix genes overexpression was accompanied by reduced matrix deposition and reduction in liver function deterioration, as assessed by bilirubin and liver enzyme levels[2].