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001-es BibID:BIBFORM077899
035-os BibID:(PMID)29278207 (WoS)000432247500002 (Scopus)85048878557
Első szerző:Nánási Péter Pál ifj. (sejtbiológus)
Cím:Omecamtiv Mecarbil : a Myosin Motor Activator Agent with Promising Clinical Performance and New in vitro Results / Péter Nánási Jr., István Komáromi, Marta Gaburjakova, János Almássy
Dátum:2018
ISSN:0929-8673
Megjegyzések:Abstract: Background: Clinical treatment of heart failure is still suffering from limited efficacy and unfavorable side effects. The recently developed group of agents, the myosin motor activators, act directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. The lead molecule, omecamtiv mecarbil is now in human 3 stage. In addition tothe promising clinical data published so far, there are new in vitro results indicating that the effect of omecamtiv mecarbil on contractility is rate-dependent. Furthermore, omecamtiv mecarbilwas shown to activate cardiac ryanodine receptors, an effect that may carry proarrhythmic risk. Methods: These new results, together with the controversial effects of the drug on cardiac oxygen consumption, are critically discussed in this review in light of the current literature on omecamtiv mecarbil. Results: In therapeutically relevant concentrations the beneficial inotropic effect of the agent isnot likely affected by these new results - in accordance with the good clinical data. At supratherapeutic concentrations, however, activation of cardiac ryanodine receptors may increasearrhythmia propensity, and the stronger effect on diastolic than systolic cell shortening, observed at higher pacing frequencies, may decrease or offset the inotropic effect of omecamtivmecarbil. Conclusion: Further studies with definitely supratherapeutical concentrations of omecamtivmecarbil should be designed to map the actual risk of these potentially harmful side-effects.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Heart failure
inotropic agents
myosin activators
Omecamtiv mecarbil
Ryanodine receptor
Cytosolic Ca 2+
Megjelenés:Current Medicinal Chemistry. - 25 : 15 (2018), p. 1720-1728. -
További szerzők:Komáromi István (1957-) (vegyész, molekuláris biológus, biokémikus) Gaburjakova, Marta Almássy János (1981-) (élettanász, biológus, angol-magyar szakfordító)
Pályázati támogatás:NKFIH PD112199
NKFIH
Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences
MTA
Szodoray Scholarship of the University of Debrecen
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2.

001-es BibID:BIBFORM077837
035-os BibID:(PMID)29792814 (WoS)000438114100006 (Scopus)85049826983
Első szerző:Nánási Péter Pál ifj. (sejtbiológus)
Cím:Perspectives of a myosin motor activator agent with increased selectivity / Péter Nánási Jr., István Komáromi, János Almássy
Dátum:2018
ISSN:0008-4212
Megjegyzések:Clinical treatment of heart failure is still not fully solved. A novel class of agents, the myosin motor activators, acts directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. Omecamtiv mecarbil, the lead molecule of this group, is now in human 3 phase displaying promising clinical performance. However, omecamtiv mecarbil is not selective to myosin, since it readily binds to and activates cardiac ryanodine receptors (RyR-2), an effect that may cause complications is case of overdose. In this study, in silico analysis was performed to investigate the docking of omecamtiv mecarbil and other structural analogues to cardiac myosin heavy chain and RyR-2 in order to select the structure which has a higher selectivity to myosin over RyR-2. In silico docking studies revealed that omecamtiv mecarbil has comparable affinity to myosin and RyR-2: the respective K values are 0.60 and 0.87 ?M. Another compound CK-1032100 has much lower affinity to RyR-2 than omecamtiv mecarbil, while it still has a moderate affinity to myosin. It was concluded that further research starting from the chemical structure of CK-1032100 may result a better myosin activator burdened probably less by the RyR-2 binding side effect. It also is possible, however, that the selectivity of omecamtiv mecarbil to myosin over RyR-2 cannot be substantially improved, because similar moieties seem to be responsible for the high affinity to both myosin and RyR-2.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Inotropic agents
Myosin activators
Omecamtiv mecarbil
Ryanodine receptor
Cytosolic Ca 2+
Megjelenés:Canadian Journal of Physiology and Pharmacology. - 96 : 7 (2018), p. 676-680. -
További szerzők:Komáromi István (1957-) (vegyész, molekuláris biológus, biokémikus) Almássy János (1981-) (élettanász, biológus, angol-magyar szakfordító)
Pályázati támogatás:NKFIH PD112199
Egyéb
Internet cím:Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
Borító:
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