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    Vericiguat

    ACTIVE PHARMA INGREDIENTS

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    2D Structure
    Also known as: 1350653-20-1, Verquvo, Methyl (4,6-diamino-2-(5-fluoro-1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)carbamate, Mk-1242, Vericiguat [inn], Bay-1021189
    Molecular Formula
    C19H16F2N8O2
    Molecular Weight
    426.4  g/mol
    InChI Key
    QZFHIXARHDBPBY-UHFFFAOYSA-N
    FDA UNII
    LV66ADM269
    Vericiguat is a direct stimulator of soluble guanylate cyclase (sGC) used in the management of systolic heart failure to reduce mortality and hospitalizations. 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). 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. 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. 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. Although not the first sGC stimulator to be granted FDA approval ([riociguat] was approved in 2013 for use in pulmonary hypertension), vericiguat is unique amongst its peers in that modifications to its structure have dramatically decreased its susceptibility to oxidative metabolism, resulting in a relatively long half-life and allowing for once-daily dosing.
    Vericiguat is a Soluble Guanylate Cyclase Stimulator. The mechanism of action of vericiguat is as a Guanylate Cyclase Stimulator.
    1 2D Structure

    2D Structure

    2 Identification
    2.1 Computed Descriptors
    2.1.1 IUPAC Name
    methyl N-[4,6-diamino-2-[5-fluoro-1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]carbamate
    2.1.2 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)
    2.1.3 InChI Key
    QZFHIXARHDBPBY-UHFFFAOYSA-N
    2.1.4 Canonical SMILES
    COC(=O)NC1=C(N=C(N=C1N)C2=NN(C3=C2C=C(C=N3)F)CC4=CC=CC=C4F)N
    2.2 Other Identifiers
    2.2.1 UNII
    LV66ADM269
    2.3 Synonyms
    2.3.1 MeSH Synonyms

    1. Bay 1021189

    2. Verquvo

    2.3.2 Depositor-Supplied Synonyms

    1. 1350653-20-1

    2. Verquvo

    3. Methyl (4,6-diamino-2-(5-fluoro-1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)carbamate

    4. Mk-1242

    5. Vericiguat [inn]

    6. Bay-1021189

    7. Bay 1021189

    8. Vericiguat [usan]

    9. Bay1021189

    10. Lv66adm269

    11. Methyl N-[4,6-diamino-2-[5-fluoro-1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]carbamate

    12. Methyl (4,6-diamino-2-(5-fluoro-1-((2-fluorophenyl)methyl)-1h-pyrazolo(3,4-b)pyridin-3-yl(pyrimidin-5-yl)carbamate

    13. Methyl (4,6-diamino-2-(5-fluoro-1-(2-fluorobenzyl)-1h-pyrazolo(3,4-b)pyridin-3-yl)pyrimidin-5-yl)carbamate

    14. Methyl N-(4,6-diamino-2-(5-fluoro-1-(2-fluorobenzyl)-1h-pyrazolo(3,4-b)pyridin-3-yl)pyrimidin-5-yl)carbamate

    15. Unii-lv66adm269

    16. Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

    17. Vericiguatum

    18. Vericiguat [jan]

    19. Vericiguat [usan:inn]

    20. Vericiguat [who-dd]

    21. Bay1021189; Verquvo

    22. Schembl429958

    23. Vericiguat (jan/usan/inn)

    24. Chembl4066936

    25. Vericiguat [orange Book]

    26. Gtpl10010

    27. Chebi:142432

    28. Dtxsid001318361

    29. Bcp18886

    30. Ex-a4694

    31. Who 9805

    32. Mfcd28502029

    33. S9693

    34. Zinc72318626

    35. Cs-6981

    36. Db15456

    37. Sb16806

    38. Ac-36737

    39. Hy-16774

    40. Bay1021189bay1021189

    41. J3.590.750e

    42. D11051

    43. P14957

    44. A887763

    45. Q27283201

    46. Bay1021189; Bay 1021189; Bay-1021189; Bay10-21189; Bay-10-21189; Bay 10-21189

    47. Methyl 4,6-diamino-2-(5-fluoro-1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate

    48. Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

    2.4 Create Date
    2011-12-26
    3 Chemical and Physical Properties
    Molecular Weight 426.4 g/mol
    Molecular Formula C19H16F2N8O2
    XLogP31.5
    Hydrogen Bond Donor Count3
    Hydrogen Bond Acceptor Count10
    Rotatable Bond Count5
    Exact Mass426.13642811 g/mol
    Monoisotopic Mass426.13642811 g/mol
    Topological Polar Surface Area147 Ų
    Heavy Atom Count31
    Formal Charge0
    Complexity622
    Isotope Atom Count0
    Defined Atom Stereocenter Count0
    Undefined Atom Stereocenter Count0
    Defined Bond Stereocenter Count0
    Undefined Bond Stereocenter Count0
    Covalently Bonded Unit Count1
    4 Drug and Medication Information
    4.1 Drug 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.

    Treatment of symptomatic chronic heart failure

    5 Pharmacology and Biochemistry
    5.1 Pharmacology

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

    5.2 FDA Pharmacological Classification
    5.2.1 Active Moiety
    VERICIGUAT
    5.2.2 FDA UNII
    LV66ADM269
    5.2.3 Pharmacological Classes
    Soluble Guanylate Cyclase Stimulator [EPC]; Guanylate Cyclase Stimulators [MoA]
    5.3 ATC Code

    C01

    C - Cardiovascular system

    C01 - Cardiac therapy

    C01D - Vasodilators used in cardiac diseases

    C01DX - Other vasodilators used in cardiac diseases

    C01DX22 - Vericiguat

    5.4 Absorption, Distribution and Excretion

    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 mcgh/L, respectively, with a Tmax of 1 hour. 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.

    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. 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.

    Volume of Distribution

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

    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.

    5.5 Metabolism/Metabolites

    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. Other identified metabolites include a denbenzylated compound and an M15 metabolite thought to be the result of oxidative metabolism, although these metabolites are poorly characterized.

    5.6 Biological Half-Life

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

    5.7 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), 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. Vericiguat directly stimulates sGC by binding to a target site on its beta-subunit, 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.