L-type calcium channel
Etripamil exerts its anti-arrhythmic effect by selectively inhibiting voltage-dependent L-type calcium channels, specifically the Cav1.2 and Cav1.3 subtypes, which are critical for mediating calcium entry into cardiac myocytes and regulating excitation-contraction coupling and nodal conduction. The compound targets L-type calcium channels expressed on atrioventricular (AV) nodal cells, arterial smooth muscles, and contractile myocardial cells. By inhibiting calcium influx through slow calcium channels in AV nodal cells, etripamil slows AV nodal conduction and prolongs the AV nodal refractory period, thereby terminating re-entrant tachyarrhythmias.

Etripamil is a novel, short-acting, nondihydropyridine L-type calcium channel blocker formulated for intranasal administration. It exerts its anti-arrhythmic effect by inhibiting voltage-dependent L-type calcium channels (Cav1.2 and Cav1.3), which are critical for mediating calcium entry into cardiac myocytes and regulating excitation-contraction coupling and nodal conduction. Specifically, etripamil targets the L-type calcium channels expressed on atrioventricular (AV) nodal cells, arterial smooth muscles, and contractile myocardial cells. By blocking calcium influx, the drug prolongs the refractory period and slows electrical conduction through the AV node, thereby interrupting the re-entrant circuits responsible for AV-nodal dependent paroxysmal supraventricular tachycardia (PSVT) and facilitating the restoration of sinus rhythm.
In vitro studies demonstrate that etripamil potently inhibits calcium influx through L-type calcium channels in a concentration-dependent manner. The compound shows high selectivity for cardiac L-type channels over other ion channels, contributing to its favorable safety profile. In cellular electrophysiology assays, etripamil reduces the amplitude of calcium currents in isolated AV nodal cells and ventricular myocytes, with rapid onset and offset kinetics consistent with its short-acting pharmacological profile.

Etripamil is a fast-acting agent with a short duration of action. Etripamil prolonged the baseline PR interval by 8% to 10% approximately five minutes following an intranasal dose of 70 mg. Clinical data shows significant efficacy in terminating arrhythmias within 15 to 60 minutes post-administration, but its effects diminish rapidly, with no significant difference in conversion rates observed by 300 minutes compared to placebo.
Etripamil is a nondihydropyridine, L-type calcium channel blocker. It is a fast-acting drug with a short duration of action. The nasal formulation of etripamil was first approved by the FDA on December 12, 2025 for the conversion of acute symptomatic episodes of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm in adults. ETRIPAMIL is a small molecule drug with a maximum clinical trial phase of III (across all indications) and has 4 investigational indications.
In vivo, etripamil has demonstrated efficacy in terminating AV nodal re-entrant tachycardia (AVNRT) and other PSVT episodes in animal models and clinical studies. When administered intranasally, the compound achieves rapid systemic absorption and produces dose-dependent slowing of AV nodal conduction. In preclinical models, etripamil effectively terminates induced tachyarrhythmias within minutes of administration, with minimal effects on blood pressure or cardiac contractility at therapeutic doses.

Non-cellular receptor binding assays for etripamil involve competitive radioligand binding displacement studies using membrane preparations from cells expressing L-type calcium channel subunits (Cav1.2 and Cav1.3). Membranes are incubated with a radiolabeled dihydropyridine calcium channel ligand (e.g., [³H]nitrendipine) and varying concentrations of etripamil. Following incubation and filtration, bound radioactivity is measured by scintillation counting. IC₅₀ values are determined from displacement curves and converted to Ki values using the Cheng-Prusoff equation.

In vitro cellular assays for etripamil involve treating isolated cardiac myocytes or cells expressing recombinant L-type calcium channels with the compound and measuring calcium channel activity using patch-clamp electrophysiology. Whole-cell voltage-clamp recordings are performed to assess the inhibition of calcium currents. Cells are held at a holding potential of -80 mV and depolarized to various test potentials in the presence of increasing concentrations of etripamil. The reduction in peak calcium current amplitude is quantified to construct concentration-response curves and determine IC₅₀ values.

Objectives: The purpose of this study was to assess the efficacy and safety of etripamil nasal spray, a short-acting calcium-channel blocker, for the rapid termination of paroxysmal supraventricular tachycardia (SVT).
Methods: This phase 2 study was performed during electrophysiological testing in patients with previously documented SVT who were induced into SVT prior to undergoing a catheter ablation. Patients in sustained SVT for 5 min received either placebo or 1 of 4 doses of active compound. The primary endpoint was the SVT conversion rate within 15 min of study drug administration. Secondary endpoints included time to conversion and adverse events. [1]
In vivo animal experiments with etripamil are conducted in large animal models of PSVT, such as pigs or dogs with inducible AV nodal re-entrant tachycardia. Animals are anesthetized and instrumented with intracardiac electrophysiology catheters to record atrial and ventricular electrograms. Tachyarrhythmias are induced by programmed electrical stimulation, and etripamil is administered intranasally at escalating doses. The primary endpoint is the time to termination of tachycardia, with secondary endpoints including AV nodal conduction parameters (AH interval, Wenckebach cycle length) and hemodynamic variables.

Absorption
After a single intranasal administration of 70 mg Etripamil, the mean (%CV) area under the concentration-time curve (AUC) was approximately 5461 (51.6%) ng·min/mL, and the Cmax was approximately 99 (64.6%) ng/mL. After a second intranasal administration of 70 mg Etripamil 10 minutes after the first administration, the mean (%CV) AUC was approximately 7721 (50.3%) ng·min/mL, and the Cmax was approximately 132 (59.1%) ng/mL. After a single intranasal administration of 70 mg, the median (range) Tmax was 7 minutes (3 to 20 minutes). After a second intranasal administration of 70 mg, the median Tmax was 13 minutes (3 to 35 minutes).
Excretion Route
Following a single intranasal administration of 70 mg of radiolabeled Etripamil to healthy subjects, approximately 29% of the dose is excreted in the urine (<0.05% unchanged), 26% in the feces (<0.05% unchanged), and the remainder is excreted in nasal and facial tissues. Approximately 71% of the total administered dose is excreted within 7–10 days.
Volume of Distribution
The mean apparent volume of distribution of Etripamil is approximately 2200 to 3500 L.
Protein Binding
The plasma protein binding rate of Etripamil is approximately 50%.
Metabolites/Metabolites
The metabolic pathways of Etripamil include hydrolysis, demethylation, N-dealkylation, secondary oxidation, glucuronidation, and taurine conjugation. Etripamil is primarily metabolized by blood esterases and the liver, mainly via the CYP3A4 and CYP3A5 pathways. Etripamil contains a methyl ester group, making it sensitive to esterase metabolism in the blood.
Biological Half-Life
After administration, the average concentration of Etripamil decreases to approximately 60% of its peak concentration (Cmax) at 25 minutes and to approximately 80% of Cmax at 60 minutes. Subsequently, the rate of concentration decline slows, and the half-life is approximately 2.5 hours.
Etripamil has a molecular weight of approximately 470.6 and a molecular formula of C₂₆H₃₅ClN₄O₃. It is a white to off-white solid powder with a purity of ≥98%. The compound is soluble in DMSO and other organic solvents. Following intranasal administration, etripamil achieves rapid systemic absorption with a Tₘₐₓ of approximately 10-20 minutes and a half-life of 2-3 hours. The compound is metabolized primarily by hepatic CYP450 enzymes, with metabolites excreted renally.

In preclinical toxicology studies, etripamil has demonstrated a favorable safety profile with a wide therapeutic index. The most commonly observed adverse effects in animal studies were dose-dependent decreases in blood pressure and heart rate, consistent with its calcium channel blocking activity. No significant organ toxicity or genotoxicity was observed at clinically relevant exposures. The compound is not intended for chronic use, limiting concerns about long-term safety.

[1]. Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm. J Am Coll Cardiol. 2018 Jul 31;72(5):489-497.

[2]. Milestone Pharmaceuticals Announces USAN Approval of Generic Name “Etripamil” for its Phase 2 Clinical Development Product for the Treatment of Paroxysmal Supraventricular Tachycardia.

Etripamil has been used in research trials for the treatment of paroxysmal supraventricular tachycardia (PSVT).

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Drug Indication
Treatment of supraventricular arrhythmias

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Results: A total of 104 patients were enrolled. The conversion rate of SVT to sinus rhythm was 65% to 95% in the Etripamil nasal spray group and 35% in the placebo group; the differences were statistically significant between the three highest-active-component dose groups and the placebo group (Pearson chi-square test). Among patients who converted, the median conversion time of Etripamil was <3 minutes. Adverse events were mainly related to the intranasal administration route or local irritation. Decreased blood pressure mainly occurred in the highest-dose Etripamil group. Conclusion: Etripamil nasal spray can rapidly terminate induced supraventricular tachycardia with a high conversion rate. The safety and efficacy results of this study provide guidance for future research on the self-administration of this novel intranasal calcium channel blocker to terminate supraventricular tachycardia (SVT) in real-world settings, focusing on the selection of Etripamil dosage. (Efficacy and safety of intranasal MSP-2017 [Etripamil] for the treatment of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm [NODE-1]; NCT02296190).
Etripamil is an investigational drug being developed by Milestone Pharmaceuticals for the acute treatment of PSVT. It has completed Phase 3 clinical trials, including the RAPID study, which evaluated the efficacy and safety of intranasal etripamil for self-administration in patients with PSVT. The compound has received Fast Track designation from the FDA. If approved, etripamil would represent the first patient-administered therapy for acute PSVT termination.

C27H36N2O4

452.6

452.267

C, 71.65; H, 8.02; N, 6.19; O, 14.14

1593673-23-4

2560549-35-9 (HCl); 1593673-23-4

91824132

Brown to wine red solid powder

1.1±0.1 g/cm3

593.8±50.0 °C at 760 mmHg

312.9±30.1 °C

0.0±1.7 mmHg at 25°C

1.534

4.14

0

6

13

33

645

1

O(C([H])([H])[H])C1=C(C([H])=C([H])C(=C1[H])[C@](C#N)(C([H])([H])C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])C1C([H])=C([H])C([H])=C(C(=O)OC([H])([H])[H])C=1[H])C([H])(C([H])([H])[H])C([H])([H])[H])OC([H])([H])[H]

VAZNEHLGJGSQEL-MHZLTWQESA-N

InChI=1S/C27H36N2O4/c1-20(2)27(19-28,23-11-12-24(31-4)25(18-23)32-5)14-8-15-29(3)16-13-21-9-7-10-22(17-21)26(30)33-6/h7,9-12,17-18,20H,8,13-16H2,1-6H3/t27-/m0/s1

methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-methylamino]ethyl]benzoate

MSP 2017; MSP-2017; Etripamil; 1593673-23-4; Etripamilo; (-)-MSP-2017

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Ethanol : ~120 mg/mL (~265.14 mM)

Solubility in Formulation 1: ≥ 3 mg/mL (6.63 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 3 mg/mL (6.63 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 3 mg/mL (6.63 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix well.

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 (Please use freshly prepared in vivo formulations for optimal results.)