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Structure-activity relationship and cardiac safety of 2-aryl-2-(pyridin-2-yl)acetamides as a new class of broad-spectrum anticonvulsants derived from Disopyramide
M. Dawidowski, M. Król, B. Szulczyk, A. Chodkowski, P. Podsadni, P. Konopelski, M. Ufnal, P. Szuberski, MZ. Wróbel, Y. Zhang, A. El Harchi, JC. Hancox, D. Jarkovska, E. Mistrova, J. Sviglerova, M. Štengl, GM. Popowicz, J. Turło
Bioorganic chemistry.
2020 ;
98 (-) :
103717.
[pub] 20200305
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Perzistentní odkaz
https://www.medvik.cz/link/bmc21012625
Grantová podpora
PG/12/69/29784
British Heart Foundation - United Kingdom
PG/14/61/31015
British Heart Foundation - United Kingdom
- MeSH
- acetamidy aplikace a dávkování chemie terapeutické užití MeSH
- antikonvulziva aplikace a dávkování chemie terapeutické užití MeSH
- disopyramid aplikace a dávkování chemie terapeutické užití MeSH
- elektrický šok MeSH
- injekce intraperitoneální MeSH
- injekce subkutánní MeSH
- krysa rodu rattus MeSH
- molekulární struktura MeSH
- myši MeSH
- pentylentetrazol aplikace a dávkování MeSH
- potkani Wistar MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- záchvaty chemicky indukované farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.
Citace poskytuje Crossref.org
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