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Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension

  • Joachim Mittendorf1,
  • Stefan Weigand1, 4,
  • Cristina Alonso-Alija1,
  • Erwin Bischoff2,
  • Achim Feurer1, 5,
  • Michael Gerisch3,
  • Armin Kern3,
  • Andreas Knorr2,
  • Dieter Lang3,
  • Klaus Muenter2,
  • Martin Radtke3,
  • Hartmut Schirok1,
  • Karl-Heinz Schlemmer3,
  • Elke Stahl3,
  • Alexander Straub1,
  • Frank Wunder2 and
  • Johannes-Peter Stasch2Email author
BMC Pharmacology20099(Suppl 1):P52

Published: 11 August 2009


Nitric OxideSignaling PathwayPoor PrognosisExperimental ModelTherapeutic Strategy

Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impairments of the NO-sGC signaling pathway have been implicated in the pathogenesis of cardiovascular and other diseases. Direct stimulation of sGC represents a promising therapeutic strategy particularly for the treatment of pulmonary hypertension (PH), a disabling disease associated with a poor prognosis. Previous sGC stimulators such as the pyrazolopyridines BAY 41-2272 and BAY41-8543 demonstrated beneficial effects in experimental models of PH, but were associated with unfavorable drug metabolism and pharmacokinetic (DMPK) properties. Herein we disclose an extended SAR exploration of this compound class to address these issues. Our efforts led to the identification of the potent sGC stimulator riociguat, which exhibits an improved DMPK profile and exerts strong effects on pulmonary hemodynamics and exercise capacity in patients with PH. Riociguat (BAY 63-2521) is currently being investigated in phase III clinical trials for the oral treatment of PH.

Authors’ Affiliations

Bayer Schering Pharma AG, Medicinal Chemistry Wuppertal, Pharma Research Center, Wuppertal, Germany
Bayer Schering Pharma AG, Cardiovascular Research, Pharma Research Center, Wuppertal, Germany
Bayer Schering Pharma AG, DMPK, Pharma Research Center, Wuppertal, Germany
Roche, Penzberg, Germany
Santhera Pharmaceuticals Ltd, Liestal, Switzerland


© Mittendorf et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.