Abstract
The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-activity relationships and were able to decrease oxidative metabolism significantly. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported.
MeSH terms
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Administration, Intravenous
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Administration, Oral
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Animals
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Blood Pressure / drug effects
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Chemistry Techniques, Synthetic
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Dogs
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Heart Failure / drug therapy*
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Hepatocytes / drug effects
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Heterocyclic Compounds, 2-Ring / administration & dosage
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Heterocyclic Compounds, 2-Ring / chemistry*
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Heterocyclic Compounds, 2-Ring / pharmacology*
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Humans
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Male
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NG-Nitroarginine Methyl Ester / adverse effects
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Pyrimidines / administration & dosage
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology*
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Rats, Transgenic
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Rats, Wistar
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Soluble Guanylyl Cyclase / genetics
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Soluble Guanylyl Cyclase / metabolism*
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Structure-Activity Relationship*
Substances
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Heterocyclic Compounds, 2-Ring
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Pyrimidines
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Soluble Guanylyl Cyclase
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vericiguat
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NG-Nitroarginine Methyl Ester