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The SARfaris: GPCR, Kinase, ADME

Sunday, 13 October 2013

New Drug Approvals 2013 - Pt. XVI - Riociguat (AdempasTM)

ATC code: not yet assigned
Wikipedia: Riociguat

On October 8, 2013, the FDA approved riociguat for the treatment of patients suffering from two forms of pulmonary hypertension - chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary arterial hypertension (PAH).

Pulmonary hypertension (PH) is a disease characterized by abnormally high blood pressure in the lungs, which increases the workload for the right ventricle of the heart. Some of the symptoms of PH are dizziness, shortness of breath and water deposits in the legs and joints. PH progresses slowly and can lead to severe and often fatal circulatory and respiratory complications. CTEPH is a form of PH caused by blood clots obstructing the passage of blood through the vessels in the lung, often after a pulmonary embolism has occurred. PAH on the other hand is caused by a chronic tightening or constriction of blood vessels.

Riociguat (CHEMBL2107834) is a stimulator of soluble guanylate cyclase (sGC), an ezyme that is activated by increased levels of nitric oxide (NO). Downstream signalling of increased levels of cGMP (CHEBI:28181) causes the dilation of the endothelium in blood vessels. SGc is a heterodimer consisting of an alpha- and beta-subunit. There are two known isoforms for each subunit (Uniprot-ids, alpha: P33402, Q02108 ; beta: Q02153, O75343). Stimulation of the kinase by riociguat and other sGC stimulators depends on the presence of a reduced heme group in the sGC beta-subunit. The activation of sGC by this class of compounds is synergistic with NO signalling. Some other compounds in this class are YC-1 (CHEMBL333985) and BAY 41-8543 (CHEMBL1916024). In contrast, the sGC can also be targeted through activators that work independently of NO signalling. 

Canonical SMILES: COC(=O)N(C)c1c(N)nc(nc1N)c2nn(Cc3ccccc3F)c4ncccc24
Std-InChI:  InChI=1S/C20H19FN8O2/c1-28(20(30)31-2)15-16(22)25-18(26-17(15)23)14-12-7-5-9-24-19(12)29(27-14)10-11-6-3-4-8-13(11)21/h3-9H,10H2,1-2H3,(H4,22,23,25,26)

Riociguat has a molecular weight of 422.42 Da. The calculated LogP for riociguat is 2.34 and the compound has no stereo-centers.

The compound is administered orally and was approved through the FDA priorities review program. It has a black box warning because it can harm fetuses and is therefore not prescribed to pregnant women. Other adverse effects of riociguat include headache, dizziness, indigestion, peripheral edema, nausea, diarrhea and vomiting.

Riociguat is a first-in-class compound and was developed by Bayer HealthCare Pharmaceuticals.

Riociguat will be marketed as a prescription medicine under the name Adempas.

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