Peripherally restricted ?2/?-1 subunit ligands that modulate CaV channel gating as novel antiarrhythmic drugs

ABSTRACT Sudden Cardiac DeathSCDcaused by ventricular tachycardias and fibrillationVT VFis a major world wide health problemclaiming the lives of someAmericans each yearCurrent antiarrhythmic drugAADtherapy to control VT VF is largely empirical and poorly efficacious with considerable risk of proarrhythmic effectsThere remains considerable unmet need for newsafe and effective AADs that specifically target the electrophysiological underpinnings of VT VF without compromising cardiac functionOur goal is to discover and develop a small molecule antiarrhythmic drug that will address this needMembers of the Cardiovascular Research LaboratoryCVRLat UCLADrsHrayr Karagueuzian and Riccardo Olcesehave recently advanced our understanding of the functional regulation of the voltage dependent calcium channel CaVby thesubunitand how modulation of CaVgating can reduce VT VF triggered by early afterdepolarizationsEADsThey have also demonstrated the effect of gabapentinoids as CaVchannel gating modifiersand with this uncovered their potential therapeutic application as AADsHoweverwhile efficaciousgabapentinoids also produce undesirable centrally mediated side effects that must be avoided in a well tolerated chronically dosed AADThis goal can be achieved through the design of peripherally restrictedligandsi ecompounds that are orally bioavailable but not centrally penetrantwhich we aim to discoverUnder Phase I SBIR funding and through use of our computational drug discovery platformwe identified two novel lead compounds thatbind to thesubunit of the CaVchannel complex with high affinityare substrates for the P glycoproteinP gpefflux pumphave high plasma brain concentration ratios in the mouse indicative of peripheral restrictionsuppress oxidative stress induced EADs in rabbit cardiomyocytes in vitroandconvert oxidative stress induced VT VF to sinus rhythm in a perfused isolated rat heart preparationHaving met the milestones for the Phase I program positions us to undertake the project described in this Phase II applicationlead identification and optimization studies directed toward nomination of two Advanced Candidates for exploratory preclinical safety studiesThe proposed work will further leverage our predictive modeling capabilities and focus on designing compounds that in addition to being potent for binding to thesubunit have favorable pharmacokinetic properties including the combination of oral bioavailability and peripheral restrictionclean off target profiles including limited interaction with safety relevant cardiac ion channelsdemonstrated anti arrhythmic efficacy in the rabbit cardiomyocyte and isolated rat heart models of our collaborators at the UCLA CVRLand demonstrated favorable effects on EADs and VT VF without negative impact on contractility in an innovative iPSC derived cardiomyocyte basedmatured human cardiac tissue modelBiowireIIdeveloped by TARA Biosystems NARRATIVE The ultimate objective of the proposed project is to develop a small molecule drug that will address the need for a novel well tolerated antiarrhythmic therapy for the treatment and prevention of ventricular tachycardias and fibrillationVT VFBy modulating gating of the voltage dependent calcium channel CaVthis drug is expected to suppress early afterdepolarizations and prevent VT VF with no adverse effects on cardiac function or centrally mediated side effects