Dofetilide

Dofetilide is a class III antiarrhythmic developed by Pfizer and marketed in the United States as Tikosyn. This methanesulfonanilide has the formula C19H27N3O5S2. The Dofetilide molecular weight is 441.56 g/mol, corresponding to CAS 115256-11-6. At clinically relevant concentrations, it acts predominantly on the rapid delayed rectifier potassium current, IKr.

Application of Dofetilide

Dofetilide is used as a high-affinity reference blocker in hERG/Kv11.1 electrophysiology, radioligand binding, and cardiac safety assay development. It can validate detection of potent IKr inhibition and support comparisons under matched recording conditions. Apparent potency depends on channel expression, membrane configuration, temperature, voltage protocol, and exposure time, so results from different assays should not be pooled.

In Vitro

In a mammalian cell line expressing hERG, dofetilide inhibited current with an EC50 of 12 ± 2 nM. An inside-out macropatch study using Xenopus oocytes reported an IC50 of approximately 35 nM. The difference reflects assay configuration, not a universal potency value.

Block develops after activation because channel opening provides access to the inner pore. Inactivation can stabilize the complex, while closure may trap the molecule and slow recovery. Dofetilide therefore interacts with open and inactivated hERG states rather than acting as a closed-channel blocker.

In Vivo

In two randomized studies cited in the US label, 500 mcg twice daily converted atrial fibrillation or flutter to sinus rhythm in 29–30% of participants, versus approximately 1% on placebo. Kaplan-Meier estimates for remaining in sinus rhythm at 12 months were 58% and 66%.

DIAMOND-CHF and DIAMOND-MI found no excess mortality when dosing began with inpatient monitoring and adjustment for renal function and QT response. Torsade de pointes occurred in 3.3% and 0.9% of dofetilide-treated patients, respectively. Clinical use of Pfizer Dofetilide requires controlled initiation because exposure, QT prolongation, and proarrhythmic risk are closely linked.

Biochemical and Physiological Actions

The Dofetilide chemical structure contains two methanesulfonamide groups connected through aromatic and flexible amine-containing regions. This Dofetilide molecular structure supports binding within the intracellular hERG pore. IKr inhibition delays phase 3 repolarization, prolonging action-potential duration, the refractory period, and the QT interval without materially slowing conduction. The same mechanism supports rhythm control and creates a concentration-dependent torsade de pointes risk.

Features and Benefits of Dofetilide

• Nanomolar hERG/IKr potency in established electrophysiology systems.
• High selectivity over other repolarizing potassium currents at relevant concentrations.
• Reference value for hERG assay validation and QT-liability research.
• Defined identity under CAS 115256-11-6 with extensive clinical and mechanistic data.

Before use, confirm the Dofetilide structure, identity, purity, and lot-specific analytical data against the certificate of analysis.