Summary
Liver cirrhosis is a chronic disease with high mortality rate and need for effective
pharmacological intervention. The fibrotic remodelling of liver tissue is crucially
dependent on hepatic stellate cell activation. Activation of hepatic stellate cells
is reduced by an increase in cyclic guanosine monophosphate (cGMP). Stable cGMP analogues
also reduce the contractile response of hepatic stellate cells. However, cGMP production
is downregulated in the cirrhotic liver due to the reduced activity of the endothelial
nitric oxide synthase.
Objective:
Here we report that the novel activator of soluble guanylate cyclase (sGC), BAY 60-2770
(4-({(4-carboxy-butyl)[2-(5-fluoro-2-{[4’-(trifluoromethyl) biphenyl-4-yl]methoxy}phenyl)ethyl]amino}methyl)benzoic
acid), which increases the activity of sGC in a nitric oxide-independent manner, attenuates
liver fibrosis in two rat models.
Methods:
The compound was studied in the pig serum model and the carbon tetrachloride model.
Fibrosis was assessed by estimating the increase in fibrous collagen by micromorphometry
of histological sections stained with Sirius Red/Fast Green and by measuring total
hepatic collagen.
Results:
BAY 60-2770, on a recombinant sGC reporter cell line, stimulated the luminescence
signals with an EC50 value of 5.4 ±1.2 nmol/L. In the presence of [1]
[2]
[4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ; 10 µmol/L) the EC50 was shifted to 0.39 ±0.11 nmol/L. In both fibrosis models, once daily oral administration
of BAY 60-2770 concomittantly with the fibrotic stimulus prevented 60–75% of fibrosis,
the lowest effective dose being 0.1 mg/kg in the pig serum model and 0.3 mg/kg in
the carbon tetrachloride model. The treatment was well tolerated by all animals. The
doses used were devoid of any significant influence on systemic blood pressure.
Conclusion:
Nitric oxide-independent activation of sGC might be an innovative therapeutic approach
for the treatment of liver fibrosis of necro-inflammatory and immunological origin.
Key words
BAY 60-2770, activation of soluble guanylyl cyclase, antifibrotic effect - Guanylate
cyclase, nitric oxide-independent activation, soluble - Liver fibrosis, carbon tetrachloride
induced, pig serum induced - Liver therapeutics
