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

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http://hdl.handle.net/10138/341314

Lähdeviite

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 . https://doi.org/10.1111/bph.15257

Julkaisun nimi: Discovery and characterization of ORM-11372, a novel inhibitor of the sodium-calcium exchanger with positive inotropic activity
Tekijä: 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
Tekijän organisaatio: Medicum
Department of Pharmacology
Eero Mervaala / Principal Investigator
Päiväys: 2020-12
Kieli: eng
Sivumäärä: 21
Kuuluu julkaisusarjaan: British Journal of Pharmacology
ISSN: 1476-5381
DOI-tunniste: https://doi.org/10.1111/bph.15257
URI: http://hdl.handle.net/10138/341314
Tiivistelmä: 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.
Avainsanat: *NCX
*ORM-11372
*cardiac safety
*positive inotropic effect
*sodium-calcium exchanger
Action Potentials
Animals
Calcium/metabolism
Heart Ventricles/metabolism
*Myocytes, Cardiac/metabolism
Rabbits
Rats
Sodium/metabolism
*Sodium-Calcium Exchanger
3111 Biomedicine
Vertaisarvioitu: Kyllä
Tekijänoikeustiedot: cc_by
Pääsyrajoitteet: openAccess
Rinnakkaistallennettu versio: publishedVersion


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