Discovery of Riociguat: A Potent, Oral Stimulator of Soluble Guanylate Cyclase for the Treatment of Pulmonary Hypertension
Event details
| Date | 30.04.2014 |
| Hour | 17:15 › 18:15 |
| Speaker | Prof. Joachim Mittendorf, Director of Medicinal Chemistry, Bayer Healthcare, Germany |
| Location | |
| Category | Conferences - Seminars |
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 various cardiovascular and other diseases. Direct stimulation of sGC therefore represents a promising therapeutic strategy particularly for the treatment of pulmonary hypertension (PH), a devastating disease where a markedly impaired bioactivity of NO contributes to excessive pulmonary vasoconstriction.[1]
Direct NO-independent sGC stimulation was first demonstrated in 1994 when Ko and colleagues reported cGMP-stimulating properties for benzylindazole YC-1. Our initial chemical optimization program based on YC-1 as a lead structure resulted in the identification of sGC stimulators such as pyrazolopyridine BAY 41-2272 with approximately 2-3 orders of magnitude higher potency.
BAY 41-2272 demonstrated beneficial effects in experimental models of PH, but was associated with unfavorable drug metabolism and pharmacokinetic properties. These issues were addressed in an extended exploration of the structure-activity-relationships[2] and 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. Based on robust efficacy in phase III clinical studies Riociguat was recently appoved in Canada and the U.S. for the treatment of two life-threatening forms of pulmonary hypertension.
[1] Follmann M.; Griebenow N.; Hahn M. G.; Hartung J.; Mais F.-J.; Mittendorf J.; Schaefer M.; Schirok H. Stasch J.-P., Stoll F.; Straub A. Angew. Chem. Int. Ed. 2013, 52, 9442-9462: The Chemistry and Biology of Soluble Guanylate Cyclase Stimulators and Activators.
[2] Mittendorf, J.; Weigand S.; Alonso-Alija C.; Bischoff E.; Feurer A.; Gerisch M.; Kern A.; Knorr A.; Lang D.; Muenter K.; Radtke M.; Schirok H.; Schlemmer K.-H.; Stahl, E.; Straub A.; Wunder F.; Stasch J.-P. ChemMedChem 2009, 4, 853-865.
Direct NO-independent sGC stimulation was first demonstrated in 1994 when Ko and colleagues reported cGMP-stimulating properties for benzylindazole YC-1. Our initial chemical optimization program based on YC-1 as a lead structure resulted in the identification of sGC stimulators such as pyrazolopyridine BAY 41-2272 with approximately 2-3 orders of magnitude higher potency.
BAY 41-2272 demonstrated beneficial effects in experimental models of PH, but was associated with unfavorable drug metabolism and pharmacokinetic properties. These issues were addressed in an extended exploration of the structure-activity-relationships[2] and 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. Based on robust efficacy in phase III clinical studies Riociguat was recently appoved in Canada and the U.S. for the treatment of two life-threatening forms of pulmonary hypertension.
[1] Follmann M.; Griebenow N.; Hahn M. G.; Hartung J.; Mais F.-J.; Mittendorf J.; Schaefer M.; Schirok H. Stasch J.-P., Stoll F.; Straub A. Angew. Chem. Int. Ed. 2013, 52, 9442-9462: The Chemistry and Biology of Soluble Guanylate Cyclase Stimulators and Activators.
[2] Mittendorf, J.; Weigand S.; Alonso-Alija C.; Bischoff E.; Feurer A.; Gerisch M.; Kern A.; Knorr A.; Lang D.; Muenter K.; Radtke M.; Schirok H.; Schlemmer K.-H.; Stahl, E.; Straub A.; Wunder F.; Stasch J.-P. ChemMedChem 2009, 4, 853-865.
Practical information
- General public
- Free
Organizer
- Prof. Jieping Zhu
[email protected]
Contact
- Prof. Jieping Zhu
[email protected]