title: Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension.
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.
authors.affiliation: Bayer Schering Pharma AG, Medicinal Chemistry Wuppertal, 42096 Wuppertal, Germany. joachim.mittendorf@bayerhealthcare.com
authors.forename: Joachim
authors.initials: J
authors.lastname: Mittendorf
authors.forename: Stefan
authors.initials: S
authors.lastname: Weigand
authors.forename: Cristina
authors.initials: C
authors.lastname: Alonso-Alija
authors.forename: Erwin
authors.initials: E
authors.lastname: Bischoff
authors.forename: Achim
authors.initials: A
authors.lastname: Feurer
authors.forename: Michael
authors.initials: M
authors.lastname: Gerisch
authors.forename: Armin
authors.initials: A
authors.lastname: Kern
authors.forename: Andreas
authors.initials: A
authors.lastname: Knorr
authors.forename: Dieter
authors.initials: D
authors.lastname: Lang
authors.forename: Klaus
authors.initials: K
authors.lastname: Muenter
authors.forename: Martin
authors.initials: M
authors.lastname: Radtke
authors.forename: Hartmut
authors.initials: H
authors.lastname: Schirok
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Schlemmer
authors.forename: Elke
authors.initials: E
authors.lastname: Stahl
authors.forename: Alexander
authors.initials: A
authors.lastname: Straub
authors.forename: Frank
authors.initials: F
authors.lastname: Wunder
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
mesh_terms: 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
chemical_list: 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