Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension.
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.
Mittendorf
Joachim
J
Bayer Schering Pharma AG, Medicinal Chemistry Wuppertal, 42096 Wuppertal, Germany. joachim.mittendorf@bayerhealthcare.com
Weigand
Stefan
S
Alonso-Alija
Cristina
C
Bischoff
Erwin
E
Feurer
Achim
A
Gerisch
Michael
M
Kern
Armin
A
Knorr
Andreas
A
Lang
Dieter
D
Muenter
Klaus
K
Radtke
Martin
M
Schirok
Hartmut
H
Schlemmer
Karl-Heinz
KH
Stahl
Elke
E
Straub
Alexander
A
Wunder
Frank
F
Stasch
Johannes-Peter
JP
D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D055808:Drug Discovery; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D013329:Structure-Activity Relationship
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; C450679:BAY 41-8543; D009025:Morpholines; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase