Vericiguat

Identification

Summary

Vericiguat is a soluble guanylate cyclase stimulator used to reduce heart failure-related hospitalization and cardiovascular death in patients with chronic systolic heart failure.

Brand Names
Verquvo
Generic Name
Vericiguat
DrugBank Accession Number
DB15456
Background

Vericiguat is a direct stimulator of soluble guanylate cyclase (sGC) used in the management of systolic heart failure to reduce mortality and hospitalizations.5 A key component of the NO-sGC-cGMP signaling pathway that helps to regulate the cardiovascular system, sGC enzymes are intracellular enzymes found in vascular smooth muscle cells (amongst other cell types) that catalyze the synthesis of cyclic guanosine monophosphate (cGMP) in response to activation by nitric oxide (NO).1,4 Cyclic GMP acts as a second messenger, activating a number of downstream signaling cascades that elicit a broad variety of effects, and these diverse cellular effects have implicated deficiencies in its production (primarily due to insufficient NO bioavailability) in the pathogenesis of various cardiovascular diseases.1 As a direct stimulator of sGC, vericiguat mitigates the need for a functional NO-sGC-cGMP axis and thereby helps to prevent the myocardial and vascular dysfunction associated with decreased sGC activity in heart failure.6

Vericiguat was approved by the FDA in January 2021 - developed by Merck under the brand name Verquvo - for use in certain patients with systolic heart failure.6 Although not the first sGC stimulator to be granted FDA approval (riociguat was approved in 2013 for use in pulmonary hypertension),7 vericiguat is unique amongst its peers in that modifications to its structure have dramatically decreased its susceptibility to oxidative metabolism,1 resulting in a relatively long half-life and allowing for once-daily dosing.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 426.388
Monoisotopic: 426.136428113
Chemical Formula
C19H16F2N8O2
Synonyms
  • Vericiguat
  • Vériciguat
  • Vericiguatum
External IDs
  • BAY 1021189
  • BAY-1021189
  • BAY1021189
  • MK-1242
  • WHO 9805

Pharmacology

Indication

Vericiguat is indicated in adults with symptomatic, chronic heart failure and an ejection fraction of <45% to reduce the risk of cardiovascular death and heart failure-related hospitalization following a hospitalization for heart failure or need for outpatient intravenous diuretics.5

Pharmacology
Reduce drug development failure rates
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

By directly stimulating the increased production of intracellular cyclic guanosine monophosphate (cGMP), vericiguat causes the relaxation of vascular smooth muscle and vasodilation.5 Vericiguat has a relatively long half-life (~30h) that allows for once-daily dosing.5

Animal reproduction studies have demonstrated the potential for embryo-fetal toxicity when vericiguat is administered to pregnant females - defects in major vessel and heart formation, as well as spontaneous abortions/resorptions, were observed when vericiguat was administered to pregnant rabbits during organogenesis.5 The possibility of pregnancy should be excluded prior to beginning therapy with vericiguat, and adequate contraception should be used throughout therapy and for one month following cessation of treatment.5

Mechanism of action

Heart failure (HF) involves, amongst other morphologic and physiologic changes, the impaired synthesis of nitric oxide (NO) and decreased activity of soluble guanylate cyclase (sGC). Functioning normally, NO binds to sGC and stimulates the synthesis of intracellular cyclic guanosine monophosphate (cGMP),4 a second messenger involved in the maintenance of vascular tone, as well as cardiac contractility and remodeling. Defects in this pathway are thought to contribute to the myocardial and vascular dysfunction associated with heart failure and are therefore a desirable target in its treatment.5,1

Vericiguat directly stimulates sGC by binding to a target site on its beta-subunit,4 bypassing the need for NO-mediated activation, and in doing so causes an increase in the production of intracellular cGMP that results in vascular smooth muscle relaxation and vasodilation.5

TargetActionsOrganism
AGuanylate cyclase soluble subunit beta-1
stimulator
Humans
Absorption

Following the administration of 10mg of vericiguat by mouth once daily, the average steady-state Cmax and AUC in patients with heart failure is 350 mcg/L and 6,680 mcg•h/L, respectively, with a Tmax of 1 hour.5 The absolute bioavailability of orally-administered vericiguat is approximately 93% when taken with food - co-administration with meals has been shown to reduce pharmacokinetic variability, increase Tmax to roughly 4 hours, and increase Cmax and AUC by 41% and 44%, respectively.5

Volume of distribution

In healthy subjects the steady-state volume of distribution of vericiguat is approximately 44 liters.5

Protein binding

Vericiguat is extensively (~98%) protein-bound in plasma, primarily to serum albumin.5

Metabolism

Vericiguat is primarily metabolized via phase II conjugation reactions, with CYP-mediated oxidative metabolism comprising a small (<5%) portion of its overall biotransformation. The major inactive metabolite, vericiguat N-glucuronide (M1), is formed by UGT1A9 and, to a lesser extent, UGT1A1.5 Other identified metabolites include a denbenzylated compound1 and an M15 metabolite thought to be the result of oxidative metabolism,3 although these metabolites are poorly characterized.

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Route of elimination

Following the oral administration of radiolabeled vericiguat, approximately 53% of the administered radioactivity was recovered in the urine and 45% in the feces.5 A human mass balance study found that the portion recovered in the urine comprised approximately 40.8% N-glucuronide metabolite, 7.7% other metabolites, and 9% unchanged parent drug, while virtually the entire portion recovered in the feces comprised unchanged vericiguat.3

Half-life

In patients with heart failure, the half-life of vericiguat is 30 hours.5

Clearance

Vericiguat is a low-clearance drug, with an observed plasma clearance of 1.6 L/h in healthy volunteers and 1.3 L/h in patients with systolic heart failure.5,3

Adverse Effects
Adverseeffects
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Toxicity

Data regarding overdosage with vericiguat are unavailable. Doses of up to 15mg once daily (50% greater than the recommended maintenance dose) have been studied and found to be well-tolerated. Symptoms of overdose are likely to be consistent with the adverse effect profile of vericiguat and may therefore involve significant hypotension for which symptomatic and supportive measures should be provided. Dialysis is unlikely to be of benefit in vericiguat overdose given its high degree of protein binding.5

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcebutololThe risk or severity of adverse effects can be increased when Acebutolol is combined with Vericiguat.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Vericiguat.
AliskirenThe risk or severity of adverse effects can be increased when Aliskiren is combined with Vericiguat.
AmbrisentanVericiguat may increase the hypotensive activities of Ambrisentan.
AmifostineThe risk or severity of adverse effects can be increased when Amifostine is combined with Vericiguat.
AmilorideThe risk or severity of adverse effects can be increased when Amiloride is combined with Vericiguat.
AmiodaroneThe risk or severity of adverse effects can be increased when Amiodarone is combined with Vericiguat.
AmlodipineThe risk or severity of adverse effects can be increased when Amlodipine is combined with Vericiguat.
AmobarbitalAmobarbital may increase the hypotensive activities of Vericiguat.
Amphotericin BThe risk or severity of adverse effects can be increased when Amphotericin B is combined with Vericiguat.
Interactions
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Food Interactions
  • Take with food. Administration with food has been shown to reduce pharmacokinetic variability and significantly improve absorption.

Products

Products2
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International/Other Brands
Verquvo (Merck)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VerquvoTablet, film coated5 mg/1OralMerck Sharp & Dohme Corp.2021-02-01Not applicableUS flag
VerquvoTablet, film coated2.5 mg/1OralMerck Sharp & Dohme Corp.2021-02-01Not applicableUS flag
VerquvoTablet, film coated10 mg/1OralMerck Sharp & Dohme Corp.2021-02-01Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
LV66ADM269
CAS number
1350653-20-1
InChI Key
QZFHIXARHDBPBY-UHFFFAOYSA-N
InChI
InChI=1S/C19H16F2N8O2/c1-31-19(30)25-14-15(22)26-17(27-16(14)23)13-11-6-10(20)7-24-18(11)29(28-13)8-9-4-2-3-5-12(9)21/h2-7H,8H2,1H3,(H,25,30)(H4,22,23,26,27)
IUPAC Name
methyl N-(4,6-diamino-2-{5-fluoro-1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}pyrimidin-5-yl)carbamate
SMILES
COC(=O)NC1=C(N)N=C(N=C1N)C1=NN(CC2=CC=CC=C2F)C2=C1C=C(F)C=N2

References

Synthesis Reference

Follmann M, Ackerstaff J, Redlich G, Wunder F, Lang D, Kern A, Fey P, Griebenow N, Kroh W, Becker-Pelster EM, Kretschmer A, Geiss V, Li V, Straub A, Mittendorf J, Jautelat R, Schirok H, Schlemmer KH, Lustig K, Gerisch M, Knorr A, Tinel H, Mondritzki T, Trubel H, Sandner P, Stasch JP: Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure. J Med Chem. 2017 Jun 22;60(12):5146-5161. doi: 10.1021/acs.jmedchem.7b00449. Epub 2017 Jun 12.

General References
  1. Follmann M, Ackerstaff J, Redlich G, Wunder F, Lang D, Kern A, Fey P, Griebenow N, Kroh W, Becker-Pelster EM, Kretschmer A, Geiss V, Li V, Straub A, Mittendorf J, Jautelat R, Schirok H, Schlemmer KH, Lustig K, Gerisch M, Knorr A, Tinel H, Mondritzki T, Trubel H, Sandner P, Stasch JP: Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure. J Med Chem. 2017 Jun 22;60(12):5146-5161. doi: 10.1021/acs.jmedchem.7b00449. Epub 2017 Jun 12. [Article]
  2. Tomasoni D, Adamo M, Anker MS, von Haehling S, Coats AJS, Metra M: Heart failure in the last year: progress and perspective. ESC Heart Fail. 2020 Dec 5. doi: 10.1002/ehf2.13124. [Article]
  3. Boettcher M, Gerisch M, Lobmeyer M, Besche N, Thomas D, Gerrits M, Lemmen J, Mueck W, Radtke M, Becker C: Metabolism and Pharmacokinetic Drug-Drug Interaction Profile of Vericiguat, A Soluble Guanylate Cyclase Stimulator: Results From Preclinical and Phase I Healthy Volunteer Studies. Clin Pharmacokinet. 2020 Nov;59(11):1407-1418. doi: 10.1007/s40262-020-00895-x. [Article]
  4. Friebe A, Sandner P, Schmidtko A: cGMP: a unique 2nd messenger molecule - recent developments in cGMP research and development. Naunyn Schmiedebergs Arch Pharmacol. 2020 Feb;393(2):287-302. doi: 10.1007/s00210-019-01779-z. Epub 2019 Dec 18. [Article]
  5. FDA Approved Drug Products: Verquvo (vericiguat) oral tablets [Link]
  6. BusinessWire: Merck Announces U.S. FDA Approval of VERQUVO® (vericiguat) [Link]
  7. Adempas (Riociguat) FDA Label [Link]
KEGG Drug
D11051
ChemSpider
32700337
BindingDB
50239781
RxNav
2475830
ChEBI
142432
ChEMBL
CHEMBL4066936
ZINC
ZINC000072318626
Wikipedia
Vericiguat

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentChronic Heart Failure With Reduced Ejection Fraction (HFrEF) / Heart Failure1
2CompletedTreatmentChronic Heart Failure With Preserved Ejection Fraction1
2CompletedTreatmentHeart Failure2
1CompletedBasic ScienceCoronary Artery Disease (CAD)1
1CompletedOtherHeart Failure2
1CompletedOtherPharmacokinetics1
1CompletedTreatmentCoronary Artery Disease (CAD)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral10 mg/1
Tablet, film coatedOral2.5 mg/1
Tablet, film coatedOral5 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9993476No2011-05-192031-05-19US flag
US8921377No2011-05-192031-05-19US flag
US9604948No2012-11-262032-11-26US flag
US10736896No2011-05-192031-05-19US flag
US8420656No2011-05-192031-05-19US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP2.99ChemAxon
pKa (Strongest Acidic)11.84ChemAxon
pKa (Strongest Basic)3.53ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area146.86 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity132.35 m3·mol-1ChemAxon
Polarizability40.69 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Stimulator
Curator comments
Soluble guanylate cyclase (sGC) is composed of two subunits, alpha (1 or 2) and beta - the binding site of vericiguat is believed to be found on the beta subunit.
General Function
Mediates responses to nitric oxide (NO) by catalyzing the biosynthesis of the signaling molecule cGMP.
Specific Function
Gtp binding
Gene Name
GUCY1B1
Uniprot ID
Q02153
Uniprot Name
Guanylate cyclase soluble subunit beta-1
Molecular Weight
70513.89 Da
References
  1. Friebe A, Sandner P, Schmidtko A: cGMP: a unique 2nd messenger molecule - recent developments in cGMP research and development. Naunyn Schmiedebergs Arch Pharmacol. 2020 Feb;393(2):287-302. doi: 10.1007/s00210-019-01779-z. Epub 2019 Dec 18. [Article]
  2. FDA Approved Drug Products: Verquvo (vericiguat) oral tablets [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. FDA Approved Drug Products: Verquvo (vericiguat) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. FDA Approved Drug Products: Verquvo (vericiguat) oral tablets [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: Verquvo (vericiguat) oral tablets [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Verquvo (vericiguat) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: Verquvo (vericiguat) oral tablets [Link]

Drug created on May 20, 2019 15:34 / Updated on February 21, 2021 18:55