Cristina Alonso-Alija

Design and synthesis of the first NO- and haem-independent sGC activator BAY 58–2667 for the treatment of acute decompensated heart failure

Soluble guanylate cyclase (sGC) is a signal-transduction enzyme activated by nitric oxide (NO) and plays a key role in a variety of physiological processes such as vasodilatation, antiaggregation, antiproliferation and neuronal signaling as well as in a variety of disorders of these functions. Current therapies that involve the use of organic nitrates and other NO donors have limitations, including non-specific interactions of NO with various biomolecules and lack of response and the development of tolerance [1,2]. Compounds that activate sGC in an NO-independent manner might therefore provide considerable therapeutic advantages.

Antifibrotic effects of an sGC activator in rat models of liver fibrosis

Background Liver fibrosis and cirrhosis are late complications common to liver diseases of different etiology such as viral hepatitis and alcoholic liver disease. Irrespective of the initial cause of liver disease, activation of hepatic stellate cells is a crucial step in the fibrotic pathomechanism. Activated hepatic stellate cells produce excess collagen as well as profibrotic cytokines and change to a contractile phenotype which reduces the diameter of the hepatic sinusoids. Activation of hepatic stellate cells is reduced by an increase in intracellular cyclic guanosine monophoshate (cGMP). Stable cGMP analogues also reduce the contractile response of hepatic stellate cells. However, cGMP production is downregulated in the cirrhotic liver due to reduced activity of the endothelial NO synthase. The recently discovered activators of soluble guanylate cyclase (sGC) increase cGMP production independently of NO. We therefore investigated the effects of an sGC activator in two classical rat models of liver fibrosis, the pig serum model and the carbon tetrachloride model.