Structure-Activity Relationship and Voltage Dependence for the Drug-Drug Interaction between Amiodarone Analogs and MNI-1 at the L-type Cav Channel.

The drug-drug interaction (DDI) between amiodarone (AMIO) and sofosbuvir (SOF), a direct-acting hepatitis-C NS5B nucleotide polymerase inhibitor, has been associated with severe bradyarrhythmia in patients. Recent cryo-EM data has revealed that this DDI occurs at the α-subunit of L-type Cav channels, with AMIO binding at the fenestration site and SOF [or MSD nucleotide inhibitor #1 (MNI-1): analog of SOF] binding at the central cavity of the conductance pathway. In this study, we investigated the DDI between 21 AMIO analogs, including dronedarone (DRON) and MNI-1 (or SOF) in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hCav1.2 models. Our findings indicate that among the tested AMIO analogs in hiPSC-CMs at clinically relevant concentrations, only three analogs (AA-9, AA-10, and AA-17) were able to effectively substitute for AMIO in this DDI with 1 µM MNI-1. This highlights the importance of the diethyl amino group of AMIO for interacting with MNI-1. In the hCav1.2 model, desethylamiodarone (AA-12) demonstrated synergy with 90 µM MNI-1, while three other analogs with modifications to the position of the diethyl amino group or removal of iodo groups showed weaker synergy with 90 µM MNI-1. Interestingly, DRON did not exhibit any interaction with 270 µM SOF or 90 µM MNI-1, suggesting that it could safely replace AMIO in patients requiring SOF treatment, other clinically relevant differences considered. Overall, our functional data align with the cryo-EM data, highlighting that this DDI is dependent on the structure of AMIO and cardiomyocyte resting membrane potential. SIGNIFICANCE STATEMENT: Our findings point to specific residues in the AMIO molecule playing a critical role in the DDI between AMIO and MNI-1 (SOF analog), confirming cryo-EM results. Applied at clinically relevant AMIO's concentrations or projected MNI-1's concentrations at the resting potentials mimicking the sinoatrial node, this DDI significantly slowed down or completely inhibited the beating of hiPSC-CMs. Finally, these in vitro results support the safe replacement of AMIO (Cordarone) with DRON (Multaq) for patients requiring SOF treatment, other clinical caveats considered.

Lead Optimization to Advance Protease-Activated Receptor-1 Antagonists in Early Discovery.

Vorapaxar is an approved drug for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Subsequent to the discovery of Vorapaxar, medicinal chemistry efforts were continued to identify structurally differentiated leads. Toward this goal, extensive structure-activity relationship studies using a C-ring-truncated version of Vorapaxar culminated in the discovery of three leads, represented as 13, 14, and 23. Among these leads, compound 14 possessed favorable pharmacokinetic properties and an off-target profile, which supported additional profiling in an exploratory rat toxicology study.