Riociguat
- IUPAC: Methyl-N-[4,6-Diamino-2-[1-[(2-fluorphenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methyl-carbaminat
SGC stimulators
Stimulation of soluble guanylate cyclase
Template: Infobox chemical / molecular formula search available
Riociguat (BAY 63-2521 ) is a new drug, which is currently being developed by Bayer Schering Pharma clinically. Trials with a stimulator of soluble guanylate cyclase (sGC ), an important enzyme in the nitric oxide pathway. At the moment, is being studied in clinical phase III trials, whether Riociguat (PAH ), can be used as a new drug to treat two forms of pulmonary hypertension, chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension.
- 4.4.1 Effects of riociguat on bone metabolism
- 4.4.2 interaction study with sildenafil
Discovery and development
The first nitric oxide - independent, heme -dependent guanylate cyclase stimulator YC-1, a synthetic Benzylindazolderivat, was described in 1978. The pharmacological characterization of this substance, 20 years later showed that YC-1 not only the activity of soluble guanylate cyclase increased, but also synergistically stimulated the guanylate cyclase with NO. YC-1 was, however, a relatively weak vasodilator and also showed side effects. Therefore, they started looking for other more potent and more specific guanylate cyclase stimulators from the class of indazole agents. The search resulted in the identification of BAY 41-2272 and BAY 41-8543. Both components were tested in various preclinical studies in various animal models. The results showed an improvement in the systemic arterial oxygenation. In order to optimize the pharmacological and pharmacokinetic profile, 1,000 more components have been tested, which eventually led to the discovery of riociguat. The drug reduced in animal models effectively, pulmonary hypertension, and reduced the disease-related hypertrophy of the right heart and other structural changes in the ventricle.
Chemistry and mode of action
Nitric oxide (NO ) acts as a signaling molecule in cells of the smooth muscle to cause the blood vessel extension. In patients with pulmonary arterial hypertension (PAH ) is the enzyme NO synthase, which has meant only reduced NO production is present. As a result one finds in these patients produced lower levels of cellular NO and vasoconstriction ( vasoconstriction ). NO as a signaling molecule binds to the enzyme soluble guanylate cyclase (sGC ) and induces the production of the secondary signaling molecule (second messenger ), cyclic guanosine monophosphate ( cGMP). Synthesized cGMP activates cGMP-dependent protein kinase ( protein kinase G) that regulates cytosolic calcium ion concentration. The variation of the calcium level in the cell caused by changing the actin -myosin contraction then the blood vessel extension. In the presence of PAH this pathway is disturbed because not enough NO is available, or it acts insufficient. In contrast to NO, or heme - independent sGC activators, such as Cinaciguat, riociguat acts as a direct sGC stimulator independently of NO. Furthermore Riociguat works synergistically to NO and achieved antiaggregatory, antiproliferative, and vasodilatory effects.
Pharmacology
Riociguat increases in concentrations between 0.1 and 100 mmol of the enzyme activity of sGC by up to 73 -fold. In addition Riociguat works in synergy with the NO - donor complex diethylamine / NO and can increase sGC activity in vitro to 112 -fold. A Phase I clinical study showed that Riociguat is quickly absorbed by the body and that the maximum plasma concentration is reached after about 0.5-1.5 hours. The average elimination half -life is 5-10 hours. Riociguat plasma concentrations may be relatively variable in different patients, so the dose is individually tailored to the initiation of therapy to the patient ( titration).
Clinical trials
Several clinical studies are currently underway to various aspects of riociguat investigate.
Phase I trials
First, the safety profile and the pharmacokinetic and pharmacodynamic properties of the drug was determined after administration of single oral doses of 0.25-5 mg - Riociguat. In a randomized, placebo - controlled study, 58 healthy male persons Riociguat in a form of an oral solution or tablets. The low initial dose was then increased gradually. Treated persons intolerant Riociguat well up to a dose of 2.5 mg.
Phase II studies
The first study to confirm the effect of the concept of riociguat in patients with PAH was performed in lung center of the University of Giessen. For this purpose, the safety, tolerability, and pharmacokinetic properties and parameters was evaluated in nineteen patients. The drug was well tolerated and was compared to NO longer effective and efficient. An open-label, non- controlled phase II study with 75 adult patients (42 patients with chronic thromboembolic pulmonary hypertension ( CTEPH ) and 33 patients with PAH, all assigned to the World Health Organization ( WHO) functional class II or III ) examined and evaluated the safety and tolerability of riociguat, as well as the effects of the drug on hemodynamics, exercise capacity, and the classification of patients in the respective functional class. These were administered over a period of 12 weeks riociguat three times daily. The dose was increased in 2- week intervals, three times daily 1 mg three times daily 2.5 mg. Riociguat had a favorable safety profile and significantly improved ability to exercise. Further hemodynamic parameters, such as, for example, pulmonary vascular resistance, cardiac output and arterial pressure in the pulmonary artery as compared with the output values of the patients was significantly improved. A further Phase II clinical trial was conducted in patients suffering from other forms of pulmonary hypertension, such as PH with interstitial lung disease (PH- ILD). PH -ILD is a specific expression of PH, for which there is currently no approved treatment. The study with PH -ILD patients was successfully completed in December 2009, and the safety and efficacy of riociguat in PH -ILD patients could be demonstrated.
Phase III studies
The currently ongoing Phase III clinical trials are carried out simultaneously in many centers. The study programs include two large, randomized, double-blind, placebo - controlled trials ( CHEST- 1 and PATENT -1), as well as their extension studies ( extensions ) CHEST- 2 and PATENT -2. Detailed descriptions of these studies can be found on the National Institutes of Health ( NIH) website.
CHEST
The Chronic thromboembolic pulmonary hypertension sGC stimulator Trial ( CHEST- 1) is a randomized placebo- controlled trial investigated the efficacy and safety of riociguat in patients with CTEPH (chronic thromboembolic pulmonary hypertension). After a 16 - week treatment with riociguat the load capacity is evaluated by the so-called 6- minute walk test. Patients who have undergone CHEST- 1 may participate in the open-label extension trial, CHEST -2
PATENT
Pulmonary Arterial Hypertension sGC stimulator Trial ( PATENT -1) is a randomized, placebo - controlled study examined the efficacy and safety of riociguat in patients with PAH. At baseline and at the end of a 12-week treatment Riociguat the ability to exercise is evaluated by means of the 6- minute walk distance. The extension of this study called PATENT -2 is offered to patients after completion of PATENT -1. This study is ongoing.
Further studies
Effects on bone metabolism of riociguat
This randomized, double-blind, placebo - controlled clinical phase I study investigated the effect of Riociguat treatment on bone metabolism. In this case, the patient is administered twice daily for 14 days 2.5 mg riociguat in the form of tablets. Data collection should be completed by the end of 2009.
Interaction study with sildenafil
This study investigated the safety, tolerability and pharmacokinetics, as well as pulmonary and systemic hemodynamic parameters of a single dose of 0.5 mg or 1 mg riociguat in patients who permanently with sildenafil (20 mg twice daily) should be treated. The study was completed in August 2009, but the results are pending.