Abstract:
: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 BAY 41-8543 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 is currently being investigated in phase III clinical trials for the oral treatment of PH.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
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 KH,Stahl E,Straub A,Wunder F,Stasch JPdoi
10.1002/cmdc.200900014subject
Has Abstractpub_date
2009-05-01 00:00:00pages
853-65issue
5eissn
1860-7179issn
1860-7187journal_volume
4pub_type
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