Discovery and characterization of ORM-11372, a unique and positively inotropic sodium-calcium exchanger/inhibitor

Otsomaa, Leena and Levijoki, Jouko and Wohlfahrt, Gerd and Chapman, Hugh and Koivisto, Ari-Pekka and Syrjanen, Kaisa and Koskelainen, Tuula and Peltokorpi, Saara-Elisa and Finckenberg, Piet and Heikkila, Aira and Najah, Abi-Gerges and Ghetti, Andre and Miller, Paul, E. and Page, Guy and Mervaala, Eero and Nagy, Norbert and Kohajda, Zsófia and Jost, Norbert and Virág, László and Varró, András and Julius, Papp (2020) Discovery and characterization of ORM-11372, a unique and positively inotropic sodium-calcium exchanger/inhibitor. British Journal of Pharmacology. ISSN 0007-1188 (In Press)

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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.

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