gw-6604 and Acute-Disease

Inhibitors of transforming growth factor beta (TGF-beta) type I receptor (ALK5) offer a novel approach for the treatment of fibrotic diseases such as renal, hepatic, and pulmonary fibrosis. The optimization of a novel phenylpyridine pyrazole series (1a) led to the identification of potent, selective, and orally active ALK5 inhibitors. The cellular potency and pharmacokinetics profiles of these derivatives were improved and several compounds presented antifibrotic activity when orally administered to rats in an acute liver model of dimethylnitrosamine- (DMN-) induced expression of collagen IA1 mRNA, a major gene contributing to excessive extra cellular matrix deposit. One of the most potent ALK5 inhibitors identified in this chemical series, compound 13d (GW788388), reduced the expression of collagen IA1 by 80% at a dose of 1 mg/kg twice a day (b.i.d.). This compound significantly reduced the expression of collagen IA1 mRNA when administered orally at 10 mg/kg once a day (u.i.d.) in a model of puromycin aminonucleoside-induced renal fibrosis.

Topics: Activin Receptors, Type I; Acute Disease; Administration, Oral; Animals; Benzamides; Collagen Type I; Collagen Type I, alpha 1 Chain; Dimethylnitrosamine; Fibrosis; Kidney; Liver Cirrhosis; Male; Models, Molecular; Protein Serine-Threonine Kinases; Puromycin Aminonucleoside; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; RNA, Messenger; Structure-Activity Relationship

1 Chronic liver disease is characterized by an exacerbated accumulation of matrix, causing progressive fibrosis, which may lead to cirrhosis. Transforming growth factor beta (TGF-beta), a well-known profibrotic cytokine, transduces its signal through the ALK5 ser/thr kinase receptor, and increases transcription of different genes including PAI-1 and collagens. The identification of GW6604 (2-phenyl-4-(3-pyridin-2-yl-1H-pyrazol-4-yl)pyridine), an ALK5 inhibitor, allowed us to evaluate the therapeutic potential of inhibiting TGF-beta pathway in different models of liver disease. 2 A cellular assay was used to identify GW6604 as a TGF-beta signaling pathway inhibitor. This ALK5 inhibitor was then tested in a model of liver hepatectomy in TGF-beta-overexpressing transgenic mice, in an acute model of liver disease and in a chronic model of dimethylnitrosamine (DMN)-induced liver fibrosis. 3 In vitro, GW6604 inhibited autophosphorylation of ALK5 with an IC(50) of 140 nM and in a cellular assay inhibited TGF-beta-induced transcription of PAI-1 (IC(50): 500 nM). In vivo, GW6604 (40 mg kg(-1) p.o.) increased liver regeneration in TGF-beta-overexpressing mice, which had undergone partial hepatectomy. In an acute model of liver disease, GW6604 reduced by 80% the expression of collagen IA1. In a chronic model of DMN-induced fibrosis where DMN was administered for 6 weeks and GW6604 dosed for the last 3 weeks (80 mg kg(-1) 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. 4 Our results suggest that inhibition of ALK5 could be an attractive new approach to treatment of liver fibrotic diseases by both preventing matrix deposition and promoting hepatocyte regeneration.

Topics: Activin Receptors, Type I; Acute Disease; Animals; Cell Line, Tumor; Chronic Disease; Dimethylnitrosamine; Hepatectomy; Humans; Liver Cirrhosis; Liver Regeneration; Male; Mice; Mice, Transgenic; Phosphorylation; Plasminogen Activator Inhibitor 1; Protein Serine-Threonine Kinases; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Signal Transduction; Transcription, Genetic; Transforming Growth Factor beta