Delving into the Latest Updates on Encainide Hydrochloride with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

(±)-2'-[2-(1-methyl-2-piperidyl)ethyl]-p-anisanilide, (±)-4-methoxy-N-(2-(2-(1-methyl-2-piperidinyl)ethyl)phenyl)benzamide, 4-Methoxy-N-{2-[2-(1-methyl-piperidin-2-yl)-ethyl]-phenyl}-benzamide

+ [6]

Target

SCNA

Action

blockers

Mechanism

SCNA blockers(Sodium channel alpha subunit blockers)

Therapeutic Areas

Cardiovascular Diseases

Active Indication

Tachycardia, VentricularVentricular Premature Complexes

Inactive Indication-

Originator Organization

Bristol Myers Squibb Co.

Active Organization

Bristol-Myers Ltd.

Inactive Organization-

Drug Highest PhaseApproved

First Approval Date

United States (24 Dec 1986),

Tachycardia, VentricularVentricular Premature Complexes

Regulation-

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Structure/Sequence

Molecular FormulaC22H29ClN2O2

InChIKeyOJIIZIWOLTYOBS-UHFFFAOYSA-N

CAS Registry66794-74-9

View All Structures (2)

Voltage-dependent K⁺ (Kv) channels are widely expressed on vascular smooth muscle cells and regulate vascular tone. Here, we explored the inhibitory effect of encainide, a class Ic anti-arrhythmic agent, on Kv channels of vascular smooth muscle from rabbit coronary arteries. Encainide inhibited Kv channels in a concentration-dependent manner with an IC₅₀ value of 8.91 ± 1.75 μM and Hill coefficient of 0.72 ± 0.06. The application of encainide shifted the activation curve toward a more positive potential without modifying the inactivation curve, suggesting that encainide inhibited Kv channels by altering the gating property of channel activation. The inhibition by encainide was not significantly affected by train pulses (1 and 2 Hz), indicating that the inhibition is not use (state)-dependent. The inhibitory effect of encainide was reduced by pretreatment with the Kv1.5 subtype inhibitor. However, pretreatment with the Kv2.1 subtype inhibitor did not alter the inhibitory effects of encainide on Kv currents. Based on these results, encainide inhibits vascular Kv channels in a concentration-dependent and use (state)-independent manner by altering the voltage sensor of the channels. Furthermore, Kv1.5 is the main Kv subtype involved in the effect of encainide.

01 Apr 2023·The American Journal of Cardiology

Perspective on Antiarrhythmic Drug Combinations

Review

Author: Reiffel, James A ; Robinson, Victoria M ; Kowey, Peter R

Physicians use multiple drugs in combination to treat hypertension, heart failure, diabetes mellitus, angina, hyperlipidemia, and many other cardiovascular conditions and risk factors. However, administering antiarrhythmic drugs (AAD) in combination is rarely discussed. Yet, the possibility of increasing efficacy and/or tolerance and/or safety of AADs (by adding mechanisms, offsetting adverse mechanisms, and/or using lower doses) exists. Unfortunately, this topic has not been reviewed in any contemporary cardiac literature of which we are aware, although information regarding AAD combinations has been published. In conclusion, and accordingly, this review discusses the possibility of using AAD combinations for both ventricular arrhythmias and atrial fibrillation, in which the rationale for such combinations, considerations for such combinations, and supporting literature are covered.

01 Aug 2022·Drug Metabolism and Disposition

Application of Empirical Scalars To Enable Early Prediction of Human Hepatic Clearance Using In Vitro-In Vivo Extrapolation in Drug Discovery: An Evaluation of 173 Drugs

Article

Author: Yan, Zhengyin ; Brown, Suzanne ; Liu, Ning ; Chang, Jae H ; Broccatelli, Fabio ; Kenny, Jane R ; Jones, Robert S ; Leung, Christian

The utilization of in vitro data to predict drug pharmacokinetics (PK) in vivo has been a consistent practice in early drug discovery for decades. However, its success is hampered by mispredictions attributed to uncharacterized biological phenomena/experimental artifacts. Predicted drug clearance (CL) from experimental data (i.e. hepatocyte intrinsic clearance: CL_int, fraction unbound in plasma: f_u,p) is often systematically underpredicted using the well-stirred model (WSM). The objective of this study was to evaluate using empirical scalars in the WSM to correct for CL mispredictions. Drugs (N=28) were used to generate numerical scalars on CL_int (α), and f_u,p (β) to minimize the error (AAFE) for CL predictions. These scalars were validated using an additional dataset (N=28 drugs) and applied to a non-redundant AstraZeneca (AZ) dataset available in the literature (N=117 drugs) for a total of 173 compounds. CL predictions using the WSM were improved for most compounds using an α value of 3.66 (~64%<2-fold) compared to no scaling (~46%<2-fold). Similarly, using a β value of 0.55 or combination of α and β scalars (values of 1.74 and 0.66, respectively) resulted in a similar improvement in predictions (~64%<2-fold and ~65%<2-fold, respectively). For highly bound compounds (f_u,p{less than or equal to}0.01), AAFE was substantially reduced across all scaling methods. Using the β scalar alone or a combination of α and β appeared optimal; and produce larger magnitude corrections for highly-bound compounds. Some drugs are still disproportionally mispredicted, however the improvements in prediction error and simplicity of applying these scalars suggests its utility for early-stage CL predictions. Significance Statement In early drug discovery, prediction of human clearance using in vitro experimental data plays an essential role in triaging compounds prior to in vivo studies. These predictions have been systematically underestimated. Here we introduce empirical scalars calibrated on the extent of plasma protein binding that appear to improve clearance prediction across multiple datasets. This approach can be used in early phases of drug discovery prior to the availability of pre-clinical data for early quantitative predictions of human clearance.

100 Deals associated with Encainide Hydrochloride

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