Discovery and characterization of ORM-11372, a novel inhibitor of the sodium-calcium exchanger with positive inotropic activity.

Leena Otsomaa,Tuula Koskelainen,Piet Finckenberg,Aira Heikkilä,Saara‐Elisa Peltokorpi,Eero Mervaala,András Varró,Gerd Wohlfahrt,Andre Ghetti,László Virág,Hugh Chapman,Jouko Levijoki,Najah Abi‐Gerges,Paul E Miller,Julius Gy Papp,Norbert Nagy,Norbert Jost,Zsófia Kohajda,Guy Page,Karí Syrjänen ,Ari Koivisto

doi:10.1111/bph.15257

Abstract

Background and PurposeThe lack of selective sodium–calcium exchanger (NCX) inhibitors has hampered the exploration of physiological and pathophysiological roles of cardiac NCX 1.1. We aimed to discover more potent and selective drug like NCX 1.1 inhibitor.Experimental ApproachA flavan series‐based pharmacophore model was constructed. Virtual screening helped us identify a novel scaffold for NCX inhibition. A distinctively different NCX 1.1 inhibitor, ORM‐11372, was discovered after lead optimization. Its potency against human and rat NCX 1.1 and selectivity against other ion channels was assessed. The cardiovascular effects of ORM‐11372 were studied in normal and infarcted rats and rabbits. Human cardiac safety was studied ex vivo using human ventricular trabeculae.Key ResultsORM‐11372 inhibited human NCX 1.1 reverse and forward currents; IC50 values were 5 and 6 nM respectively. ORM‐11372 inhibited human cardiac sodium 1.5 (I Na) and hERG KV11.1 currents (I hERG) in a concentration‐dependent manner; IC50 values were 23.2 and 10.0 μM. ORM‐11372 caused no changes in action potential duration; short‐term variability and triangulation were observed for concentrations of up to 10 μM. ORM‐11372 induced positive inotropic effects of 18 ± 6% and 35 ± 8% in anaesthetized rats with myocardial infarctions and in healthy rabbits respectively; no other haemodynamic effects were observed, except improved relaxation at the lowest dose.Conclusion and ImplicationsORM‐11372, a unique, novel, and potent inhibitor of human and rat NCX 1.1, is a positive inotropic compound. NCX inhibition can induce clinically relevant improvements in left ventricular contractions without affecting relaxation, heart rate, or BP, without pro‐arrhythmic risk.

Highlights

The sodium–calcium exchangers (NCX; SLC8) play dynamic roles in excitation–contraction coupling (ECC) in cardiomyocytes (CMs)
Animal studies are reported in compliance with the ARRIVE guidelines (Percie du Sert et al, 2020) and with the recommendations made by the British Journal of Pharmacology (Lilley et al, 2020)
The first NCX inhibitor, exchanger-inhibiting peptide (XIP), was a peptide, it enabled us to study the role of NCX under physiological and pathological conditions in cells and isolated tissues (Hobai et al, 1997)

Summary

Introduction

The sodium–calcium exchangers (NCX; SLC8) play dynamic roles in excitation–contraction coupling (ECC) in cardiomyocytes (CMs). Selective NCX inhibitors have only minor effect on peak [Ca2+]i in mice and dogs (Kohajda et al, 2016; Kormos et al, 2014; Oravecz et al, 2018). Both mechanical relaxation and [Ca2+]i decay remained unchanged (Kormos et al, 2014). Selective NCX inhibitors either slightly shorten action potential (AP) duration or have no effect in normal oxygen and ionic conditions. Key Results: ORM-11372 inhibited human NCX 1.1 reverse and forward currents; IC50 values were 5 and 6 nM respectively.

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