Nitric oxide-independent activation of soluble guanylate cyclase by BAY 60-2770 in experimental liver fibrosis.
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-carboxybutyl) [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 pmol/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.


CONCLUSIONS
Nitric oxide-independent activation of sGC might be an innovative therapeutic approach for the treatment of liver fibrosis of necro-inflammatory and immunological origin.
Knorr
Andreas
A
Institute of Cardiovascular Research, Bayer HealthCare AG, Wuppertal, Germany. andreas.knorr@bayerhealthcare.com
Hirth-Dietrich
Claudia
C
Alonso-Alija
Cristina
C
Härter
Michael
M
Hahn
Michael
M
Keim
Yvonne
Y
Wunder
Frank
F
Stasch
Johannes-Peter
JP
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control; D002626:Chemistry, Pharmaceutical; D003094:Collagen / Q000096:biosynthesis; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D044967:Serum; D000071756:Soluble Guanylyl Cyclase; D013552:Swine
C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; D001565:Benzoates; D001713:Biphenyl Compounds; D020536:Enzyme Activators; D006845:Hydrocarbons, Fluorinated; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D003094:Collagen; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006909:Hydroxyproline