| Identification | Back Directory | [Name]
vericiguat | [CAS]
1350653-20-1 | [Synonyms]
MK-1242
vericiguat
BAY1021189
Avatrombopag Maleate
Vericiguat (BAY 1021189)
Methyl (4,6-diamino-2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)carbamate
Carbamic acid, N-[4,6-diamino-2-[5-fluoro-1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-, methyl ester | [Molecular Formula]
C19H16F2N8O2 | [MDL Number]
MFCD28502029 | [MOL File]
1350653-20-1.mol | [Molecular Weight]
426.38 |
| Chemical Properties | Back Directory | [Boiling point ]
535.9±50.0 °C(Predicted) | [density ]
1.63±0.1 g/cm3(Predicted) | [solubility ]
DMSO:60.0(Max Conc. mg/mL);140.7(Max Conc. mM) | [form ]
A solid | [pka]
10.61±0.70(Predicted) | [color ]
Light yellow to brown | [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) | [InChIKey]
QZFHIXARHDBPBY-UHFFFAOYSA-N | [SMILES]
C(OC)(=O)NC1=C(N)N=C(C2C3=CC(F)=CN=C3N(CC3=CC=CC=C3F)N=2)N=C1N |
| Hazard Information | Back Directory | [Description]
Vericiguat is a novel oral soluble guanylate cyclase (sGC) stimulator.
- Soluble guanylate cyclase (sGC) is an enzyme that is activated by nitric oxide (NO). The activation initiates a signaling cascade which converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP levels increase & protein kinase G (PKG) is activated, resulting in a decrease of intracellular free Ca++ -> vascular smooth muscle cell relaxation.
- However, individuals with HF have reduced NO levels. Vericiguat, as a sGC stimulator, increases the enzymatic activity of sGC to generate cGMP independently of NO and enhances sGC sensitivity to endogenous NO.
Vericiguat is the 2nd drug in this class and follows riociguat ADEMPAS, which has been approved for treating pulmonary arterial hypertension.
SOCRATES-REDUCED was a phase II dose-finding trial of vericiguat in HF-rEF. The primary endpoint, change in NTproBNP over 12 weeks, was not statistically significant compared to placebo. A secondary exploratory analysis suggested a dose-response relationship in which higher doses of vericiguat were associated with greater reductions in NTproBNP levels. | [Uses]
Vericiguat is a novel oral soluble guanylate cyclase (sGC) stimulator that enhances the cyclic guanosine monophosphate (GMP) production pathway, by directly stimulating soluble guanylate cyclase activity, as well as sensitizing soluble guanylate cyclase to endogenous NO. It was initially developed for potential to reduce mortality and morbidity associated with chronic heart failure with reduced ejection fraction. | [Definition]
ChEBI: Vericiguat is a pyrazolopyridine that is 5-fluoro-1H-pyrazolo[3,4-b]pyridine in which the amino hydrogen at position 1 has been substituted by a 2-fluorobenzyl group and the hydrogen at position 3 has been substituted by a 4,6-diamino-5-[(methoxycarbonyl)amino]pyrimidin-2-yl group. It is a soluble guanylate cyclase stimulator which is used for treatment of chronic heart failure. It has a role as a soluble guanylate cyclase activator, a vasodilator agent and an antihypertensive agent. It is an aminopyrimidine, a pyrazolopyridine, a carbamate ester and an organofluorine compound. | [Mechanism of action]
Vericiguat stimulates sGC, which increases cGMP production even when nitric oxide (NO) levels in the body are low. The NO-sGC-cGMP pathway is a key signaling pathway in the cardiovascular system, closely related to vasodilation, blood pressure regulation, and heart function. In patients with heart failure, this pathway may be impaired, resulting in reduced availability of NO, which in turn affects the health of the heart and blood vessels. Vericiguat helps restore the function of this pathway by mimicking the effects of NO, thereby improving the symptoms and quality of life of patients with heart failure. | [Clinical Use]
Vericiguat was advanced to clinical evaluation, as an oral therapy for chronic heart failure, either with reduced ejection fraction (HFrEF), or preserved EF (HFpEF). In mid-June 2020 Merck announced that the FDA had granted priority review status to vericiguat and based on this. The FDA approved vericiguat in January 2021, to reduce the risk of cardiovascular death, heart failure re-hospitalisation, or the requirement for outpatient intravenous diuretics, in patients with symptomatic chronic heart failure and ejection fraction less than 45%. This approval was based on efficacy data arising from the Phase 3 trial NCT02861534 (a.k.a. the VICTORIA trial). | [Synthesis]
The synthesis process of Vericiguat is to prepare intermediate 6.11 from the reaction of aniline diazonium salt (6.10) and malononitrile. The obtained dinitrile 6.11 is condensed with intermediate 6.9 in dimethylformamide (DMF) to obtain 6.12 in two steps. Next, amine (6.13) is obtained by catalytic hydrogenation reduction. Finally, methyl chloroformate reacts selectively with the amino group at the C5 position to produce Vericiguat (6) with a yield of 96%.
 | [in vivo]
Vericiguat (compound 24) (oral administration; 3 mg/kg, 10 mg/kg; once daily; 21 days) maintains heart and kidney function in a model of hypertension-induced end-organ damage in L-NAME-treated renin transgenic rats. Additionally,Vericiguat-treated group substantially reduces overall mortality when compared to the control group[1]. | Animal Model: | L-NAME-treated renin transgenic rats[1] | | Dosage: | 3 mg/kg, 10 mg/kg | | Administration: | Oral administration; 3 mg/kg, 10 mg/kg; once daily; 21 days | | Result: | Resulted in a significant attenuation of blood pressure increase, however the overall rise of blood pressure increase was not halted in the 3/10 mg/kg treatment groups.Resulted a significant and dose-dependent reduction of heart hypertrophy, in both the right and left ventricle.With respect to kidney damage, Vericiguat? Led to a significant reduction in kidney injury molecule Kim-1 and osteopontin expression which are used as biomarkers for renal injury and dysfunction.Resulted in a significant and dose-dependent increase in survival rates. The rat survival rate was 70% and 90%, respectively in the 3 and 10 mg/kg qd treatment groups. In contrast, the survival rate in the placebo group was only 25% after 21 days. |
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