Discovery and Characterization of ORM‐11372, a Novel Inhibitor of the Sodium‐Calcium Exchanger with Positive Inotropic Activity

Otsomaa, Leena and Levijoki, Jouko and Wohlfahrt, Gerd and Chapman, Hugh and Koivisto, Ari‐Pekka and Nagy, Norbert and Kohajda, Zsófia and Jost, Norbert and Virág, László and Varró, András and Papp, Julius Gy. (2020) Discovery and Characterization of ORM‐11372, a Novel Inhibitor of the Sodium‐Calcium Exchanger with Positive Inotropic Activity. BRITISH JOURNAL OF PHARMACOLOGY, 177 (24). pp. 5534-5554. ISSN 1476-5381

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Abstract

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; IC50 values were 5 and 6 nM, respectively. ORM‐11372 inhibited human cardiac sodium 1.5 (INa) and hERG KV11.1 currents (IhERG) 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 upto 10 μM. ORM‐11372 induced positive inotropic effects in 18 ± 6% and 35 ± 8% anesthetized rats with myocardial infarctions and 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 blood pressure, without pro‐arrhythmic risk.

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