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Discovery and characterization of ORM‐11372, a novel inhibitor of the sodium‐calcium exchanger with positive inotropic activity
Author(s) -
Otsomaa Leena,
Levijoki Jouko,
Wohlfahrt Gerd,
Chapman Hugh,
Koivisto AriPekka,
Syrjänen Kaisa,
Koskelainen Tuula,
Peltokorpi SaaraElisa,
Finckenberg Piet,
Heikkilä Aira,
AbiGerges Najah,
Ghetti Andre,
Miller Paul E.,
Page Guy,
Mervaala Eero,
Nagy Norbert,
Kohajda Zsófia,
Jost Norbert,
Virág László,
Varró András,
Papp Julius Gy.
Publication year - 2020
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15257
Subject(s) - inotrope , herg , sodium calcium exchanger , pharmacophore , pharmacology , chemistry , in vivo , sodium , sodium channel , calcium , ex vivo , levosimendan , medicine , potassium channel , in vitro , biochemistry , biology , microbiology and biotechnology , organic chemistry
Background and Purpose The 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 Approach A 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 Results ORM‐11372 inhibited human NCX 1.1 reverse and forward currents; IC 50 values were 5 and 6 nM respectively. ORM‐11372 inhibited human cardiac sodium 1.5 ( I Na ) and hERG K V 11.1 currents ( I hERG ) in a concentration‐dependent manner; IC 50 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 Implications ORM‐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.