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

Show simple item record Otsomaa, Leena Levijoki, Jouko Wohlfahrt, Gerd Chapman, Hugh Koivisto, Ari-Pekka Syrjänen, Kaisa Koskelainen, Tuula Peltokorpi, Saara-Elisa Finckenberg, Piet Heikkilä, Aira Abi-Gerges, Najah Ghetti, Andre Miller, Paul E Page, Guy Mervaala, Eero Nagy, Norbert Kohajda, Zsófia Jost, Norbert Virág, László Varró, András Papp, Julius Gy 2022-03-04T16:59:01Z 2022-03-04T16:59:01Z 2020-12
dc.identifier.citation Otsomaa , L , Levijoki , J , Wohlfahrt , G , Chapman , H , Koivisto , A-P , Syrjänen , K , Koskelainen , T , Peltokorpi , S-E , Finckenberg , P , Heikkilä , A , Abi-Gerges , N , Ghetti , A , Miller , P E , Page , G , Mervaala , E , Nagy , N , Kohajda , Z , Jost , N , Virág , L , Varró , A & Papp , J G 2020 , ' Discovery and characterization of ORM-11372, a novel inhibitor of the sodium-calcium exchanger with positive inotropic activity ' , British Journal of Pharmacology , vol. 177 , no. 24 , pp. 5534-5554 .
dc.identifier.other PURE: 175023715
dc.identifier.other PURE UUID: 7634ef1b-963b-4f77-824e-8ee27e65e05a
dc.identifier.other RIS: urn:0C85E84C5D36ECB092533EF50901DEC8
dc.description.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; 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. en
dc.format.extent 21
dc.language.iso eng
dc.relation.ispartof British Journal of Pharmacology
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject *NCX
dc.subject *ORM-11372
dc.subject *cardiac safety
dc.subject *positive inotropic effect
dc.subject *sodium-calcium exchanger
dc.subject Action Potentials
dc.subject Animals
dc.subject Calcium/metabolism
dc.subject Heart Ventricles/metabolism
dc.subject *Myocytes, Cardiac/metabolism
dc.subject Rabbits
dc.subject Rats
dc.subject Sodium/metabolism
dc.subject *Sodium-Calcium Exchanger
dc.subject 3111 Biomedicine
dc.title Discovery and characterization of ORM-11372, a novel inhibitor of the sodium-calcium exchanger with positive inotropic activity en
dc.type Article
dc.contributor.organization Medicum
dc.contributor.organization Department of Pharmacology
dc.contributor.organization Eero Mervaala / Principal Investigator
dc.description.reviewstatus Peer reviewed
dc.relation.issn 1476-5381
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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