Riociguat: Mode of Action and Clinical Development in Pulmonary Hypertension.
Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive and debilitating diseases characterized by gradual obstruction of the pulmonary vasculature, leading to elevated pulmonary artery pressure (PAP) and increased pulmonary vascular resistance (PVR). If untreated, they can result in death due to right-sided heart failure. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is approved for the treatment of PAH and CTEPH. We describe in detail the role of the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway in the pathogenesis of PAH and CTEPH and the mode of action of riociguat. We also review the preclinical data associated with the development of riociguat, along with the efficacy and safety data of riociguat from initial clinical trials and pivotal phase III randomized clinical trials in PAH and CTEPH.
University of Giessen and Marburg Lung Center, Giessen, Germany and the German Center for Lung Research (DZL); Department of Medicine, Imperial College London, London, England. Electronic address: ardeschir.ghofrani@innere.med.uni-giessen.de.
Hossein-Ardeschir
HA
Ghofrani
Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, DHU Thorax Innovation, Hôpital Bicêtre and Université Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique and INSERM Unité 999, Le Kremlin-Bicêtre, France.
Marc
M
Humbert
Center for Pulmonary Vascular Disease and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada.
David
D
Langleben
University of Giessen and Marburg Lung Center, Giessen, Germany and the German Center for Lung Research (DZL).
Ralph
R
Schermuly
Bayer Pharma AG, Wuppertal and University Halle, Institute of Pharmacy, Halle (Saale), Germany.
Johannes-Peter
JP
Stasch
Department of Medicine, Imperial College London, London, England.
Martin R
MR
Wilkins
Division of Pulmonary, Sleep, and Critical Care Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
James R
JR
Klinger
D002908:Chronic Disease; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011655:Pulmonary Embolism / Q000150:complications; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D015398:Signal Transduction; D016896:Treatment Outcome; D000070857:Walk Test
D011720:Pyrazoles; D011743:Pyrimidines; D009569:Nitric Oxide; D006152:Cyclic GMP; C542595:riociguat
chronic thromboembolic pulmonary hypertension; pulmonary arterial hypertension; sGC stimulator