Peripherally restricted α δ subunit ligands that modulate CaV channel gating as novel antiarrhythmic drugs

Abstract Sudden Cardiac Death SCD caused by ventricular tachycardias and fibrillation VT VF is a major world wide health problem claiming the lives of some Americans each year Current antiarrhythmic drug AAD therapy to control VT VF is largely empirical and poorly efficacious with considerable risk of proarrhythmic effects There remains considerable unmet need for new safe and effective AADs that specifically target the electrophysiological underpinnings of VT VF without compromising cardiac function Our goal is to discover and develop a small molecule antiarrhythmic drug that will address this need Members of the Cardiovascular Research Laboratory at UCLA Drs Hrayr Karagueuzian and Riccardo Olcese have recently advanced our understanding of the functional regulation of the voltage dependent calcium channel CaV by the subunit and how modulation of CaV gating can reduce VT VF triggered by early afterdepolarizations EADs They have also demonstrated the effect of gabapentinoids as CaV channel gating modifiers and with this uncovered their potential therapeutic application as AADs However while efficacious gabapentinoids also produce undesirable centrally mediated side effects that must be avoided in a well tolerated chronically dosed AAD This goal can be achieved through the design of peripherally restricted ligands i e compounds that are orally bioavailable but not centrally penetrant which we aim to discover In preliminary work Numerate has built predictive computational models for binding to and for being a substrate for the drug efflux pump P glycoprotein P gp These models will allow us to efficiently identify compounds that are likely to be peripherally restricted high affinity ligands for the gabapentinoid site on An initial in silico screen of million commercially available compounds identified a series of compounds that are predicted to be ligands for the channel subunit and that also have a high likelihood of being peripherally restricted We will select compounds from this screen for testing In this SBIR grant proposal Numerate proposes to collaborate with Drs Hrayr Karagueuzian and Riccardo Olcese at the UCLA Cardiovascular Research Laboratory in order to discover high affinity peripherally restricted ligands and demonstrate their ability to modulate CaV channel gating and suppress EAD triggered VT VF in cell based assays and an isolated intact heart model 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 fibrillation VT VF By modulating gating of the voltage dependent calcium channel CaV this drug is expected to suppress early afterdepolarizations and prevent VT VF with no adverse effects on cardiac function or centrally mediated side effects