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

被引：3

作者：

Dawidowski, Maciej ^{[1
]}

Krol, Marek ^{[1
]}

Szulczyk, Bartlomiej ^{[1
,2
]}

Chodkowski, Andrzej ^{[1
]}

Podsadni, Piotr ^{[1
]}

Konopelski, Piotr ^{[3
]}

Ufnal, Marcin ^{[3
]}

Szuberski, Piotr ^{[1
]}

Wrobel, Martyna Zofia ^{[1
]}

Zhang, Yihong ^{[4
]}

El Harchi, Aziza ^{[4
]}

Hancox, Jules C. ^{[4
]}

Jarkovska, Dagmar ^{[5
]}

Mistrova, Eliska ^{[5
]}

Sviglerova, Jitka ^{[5
]}

Stengl, Milan ^{[5
]}

Popowicz, Grzegorz M. ^{[6
]}

Turlo, Jadwiga ^{[1
]}

机构：

[1] Med Univ Warsaw, Dept Drug Technol & Pharmaceut Biotechnol, Banacha 1, PL-02097 Warsaw, Poland

[2] Med Univ Warsaw, Ctr Preclin Res, Lab Physiol & Pathophysiol, Banacha 1B, PL-02097 Warsaw, Poland

[3] Med Univ Warsaw, Ctr Preclin Res, Dept Expt Physiol & Pathophysiol, Banacha 1B, PL-02097 Warsaw, Poland

[4] Univ Bristol, Fac Med Sci, Sch Physiol Pharmacol & Neurosci, Bristol BS8 1TD, Avon, England

[5] Charles Univ Prague, Fac Med Pilsen, Biomed Ctr, Dept Physiol, Alej Svobody 1655-76, Plzen 32300, Czech Republic

[6] Helmholtz Zentrum Munchen, Inst Struct Biol, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany

来源：

BIOORGANIC CHEMISTRY | 2020年 / 98卷

关键词：

Voltage-gated sodium channel; Sodium channel blocker; Disopyramide; Drug discovery; Structure-activity relationships; Anticonvulsant agent; Refractory epilepsy; Drug repositioning; Medicinal Chemistry; Cardiac safety; PHARMACOLOGICAL CHARACTERIZATION; ANTIARRHYTHMIC-DRUGS; ANTIEPILEPTIC DRUGS; QT PROLONGATION; MODEL; INHIBITION; DISCOVERY; MEDIATION; QUINIDINE; EPILEPSY;

D O I：

10.1016/j.bioorg.2020.103717

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：14

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