122376-67-4Relevant articles and documents
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
?tengl, Milan,Chodkowski, Andrzej,Dawidowski, Maciej,El Harchi, Aziza,Hancox, Jules C.,Jarkovska, Dagmar,Konopelski, Piotr,Król, Marek,Mistrova, Eliska,Podsadni, Piotr,Popowicz, Grzegorz M.,Sviglerova, Jitka,Szuberski, Piotr,Szulczyk, Bart?omiej,Tur?o, Jadwiga,Ufnal, Marcin,Wróbel, Martyna Zofia,Zhang, Yihong
, (2020/03/17)
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.
Synthesis and pharmacology of potential cocaine antagonists. 2. Structure-activity relationship studies of aromatic ring-substituted methylphenidate analogs
Deutsch, Howard M.,Shi, Qing,Gruszecka-Kowalik, Ewa,Schwer, Margaret M.
, p. 1201 - 1209 (2007/10/03)
As part of a program, to develop medications which can block the binding of cocaine to the dopamine transporter, yet spare dopamine uptake, a series of aromatic ring-substituted methylphenidate derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Synthesis was accomplished by alkylation of 2-bromopyridine with anions derived from various substituted phenylacetonitriles. In most cases, erythro compounds were markedly less potent than the corresponding (±)-threo-methylphenidate (TMP; Ritalin) derivatives. The ortho-substituted compounds were much less potent than the corresponding meta- and/or para-substituted derivatives. The most potent compound against [3H]WIN 35,428 binding, m-bromo-TMP, was 20-fold more potent than the parent compound, whereas the most potent compound against [3H]dopamine uptake, m,p-dichloro-TMP, was 32-fold more potent. Threo derivatives with m-or p-halo substituents were more potent than TMP, while electron-donating substituants caused little change or a small loss of potency. All of the derivatives had Hill coefficients approaching unity, except m,p-dichloro-TMP, which had an nH of 2.0. Although the potency of the (±)-methylphenidate derivatives in the two assays was highly correlated (R2 = 0.986), the compounds m-chloro-, m-methyl-, and p-iodo-TMP were 4-5-fold more potent at inhibiting [3H]-WIN 35,428 binding than [3H]dopamine uptake (cocaine has a ratio of 2.3). These and other compounds may be promising candidates for further testing as potential partial agonists or antagonists of cocaine.
