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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Vericiguat (DB15456)

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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

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Associated Conditions

• Cardiovascular Mortality
• Heart Failure Hospitalization

Contraindications & Blackbox Warnings

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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

Target	Actions	Organism
AGuanylate cyclase soluble subunit beta-1	stimulator	Humans

Absorption

Following the administration of 10mg of vericiguat by mouth once daily, the average steady-state C_max and AUC in patients with heart failure is 350 mcg/L and 6,680 mcg•h/L, respectively, with a T_max 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 T_max to roughly 4 hours, and increase C_max 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.

Hover over products below to view reaction partners

• Vericiguat
  • Vericiguat N-glucuronide
  • Vericiguat debenzylated metabolite

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

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abaloparatide	The risk or severity of adverse effects can be increased when Abaloparatide is combined with Vericiguat.
Acebutolol	The risk or severity of adverse effects can be increased when Acebutolol is combined with Vericiguat.
Aldesleukin	The risk or severity of adverse effects can be increased when Aldesleukin is combined with Vericiguat.
Aliskiren	The risk or severity of adverse effects can be increased when Aliskiren is combined with Vericiguat.
Ambrisentan	Vericiguat may increase the hypotensive activities of Ambrisentan.
Amifostine	The risk or severity of adverse effects can be increased when Amifostine is combined with Vericiguat.
Amiloride	The risk or severity of adverse effects can be increased when Amiloride is combined with Vericiguat.
Amiodarone	The risk or severity of adverse effects can be increased when Amiodarone is combined with Vericiguat.
Amlodipine	The risk or severity of adverse effects can be increased when Amlodipine is combined with Vericiguat.
Amobarbital	Amobarbital may increase the hypotensive activities of Vericiguat.

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Food Interactions

• Take with food. Administration with food has been shown to reduce pharmacokinetic variability and significantly improve absorption.

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International/Other Brands

Verquvo (Merck)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Verquvo	Tablet, film coated	2.5 mg	Oral	Bayer Ag	2021-10-29	Not applicable
Verquvo	Tablet, film coated	5 mg	Oral	Bayer Ag	2021-10-29	Not applicable
Verquvo	Tablet, film coated	10 mg	Oral	Bayer Ag	2021-10-29	Not applicable
Verquvo	Tablet, film coated	5 mg/1	Oral	Merck Sharp & Dohme Llc	2021-02-01	Not applicable
Verquvo	Tablet, film coated	10 mg	Oral	Bayer Ag	2021-10-29	Not applicable
Verquvo	Tablet, film coated	2.5 mg	Oral	Bayer Ag	2021-10-29	Not applicable
Verquvo	Tablet, film coated	5 mg	Oral	Bayer Ag	2021-10-29	Not applicable
Verquvo	Tablet, film coated	2.5 mg	Oral	Bayer Ag	2021-10-29	Not applicable
Verquvo	Tablet, film coated	10 mg	Oral	Bayer Ag	2021-10-29	Not applicable
Verquvo	Tablet, film coated	2.5 mg	Oral	Bayer Ag	2021-10-29	Not applicable

Categories

ATC Codes

C01DX22 — Vericiguat

• C01DX — Other vasodilators used in cardiac diseases
• C01D — VASODILATORS USED IN CARDIAC DISEASES
• C01 — CARDIAC THERAPY
• C — CARDIOVASCULAR SYSTEM

Drug Categories

• BCRP/ABCG2 Substrates
• Cardiac Therapy
• Guanylate Cyclase Stimulators
• Heterocyclic Compounds, Fused-Ring
• Hypotensive Agents
• P-glycoprotein substrates
• Soluble Guanylate Cyclase Stimulator
• Teratogens
• UGT1A1 Substrates
• UGT1A9 Substrates
• Vasodilators Used in Cardiac Diseases

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]

External Links

KEGG Drug

D11051

ChemSpider

32700337

BindingDB

50239781

RxNav

2475830

ChEBI

142432

ChEMBL

CHEMBL4066936

ZINC

ZINC000072318626

Wikipedia

Vericiguat

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Not Yet Recruiting	Basic Science	Heart Failure	1
4	Recruiting	Treatment	Chronic Heart Failure With Reduced Ejection Fraction (HFrEF) / Worsening of heart failure	1
4	Recruiting	Treatment	Heart Failure / Hearth Failure With Reduced Ejection Fraction (HFrEF)	1
3	Completed	Treatment	Chronic Heart Failure With Reduced Ejection Fraction (HFrEF) / Heart Failure	1
3	Recruiting	Treatment	Chronic Heart Failure With Reduced Ejection Fraction (HFrEF)	1
2	Completed	Treatment	Chronic Heart Failure With Preserved Ejection Fraction	1
2	Completed	Treatment	Heart Failure	2
2	Not Yet Recruiting	Prevention	Microvascular Coronary Dysfunction (MCD) / Syndrome, Metabolic	1
2	Not Yet Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19) / Post-COVID ME/CFS	1
2, 3	Recruiting	Treatment	Heart Failure / Systolic Left Ventricular Dysfunction	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	10 mg
Tablet	Oral	2.5 mg
Tablet	Oral	5 mg
Tablet, film coated	Oral	10 MG
Tablet, film coated	Oral	10 mg/1
Tablet, film coated	Oral	2.5 mg/1
Tablet, film coated	Oral	2.5 MG
Tablet, film coated	Oral	5 mg/1
Tablet, film coated	Oral	5 MG

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9993476	No	2018-06-12	2031-05-19
US8921377	No	2014-12-30	2031-05-19
US9604948	No	2017-03-28	2032-11-26
US10736896	No	2020-08-11	2031-05-19
US8420656	No	2013-04-16	2031-05-19
US11439642	No	2011-05-19	2031-05-19

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
logP	2.99	Chemaxon
pKa (Strongest Acidic)	11.84	Chemaxon
pKa (Strongest Basic)	3.53	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	8	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	146.86 Å2	Chemaxon
Rotatable Bond Count	5	Chemaxon
Refractivity	132.35 m3·mol-1	Chemaxon
Polarizability	40.69 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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Details1. Guanylate cyclase soluble subunit beta-1

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]

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