Asymmetric synthesis and in vivo/in vitro characterization of new hybrid anticonvulsants derived from (2,5-dioxopyrrolidin-1-yl)phenylacetamides

Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides

“…In consequence, all final compounds were initially tested in the MES model after an intraperitoneal ( i.p .) administration at a screening dose of 100 mg/kg in mice (in a group consisting of four animals) and the protection against MES seizures was observed at the pretreatment time point of 0.5 h, similarly to our previous studies [ 6 , 8 ].…”

“…The next step of structural modifications involved the synthesis of compounds with an R -configuration of the asymmetric carbon atom (C1 -R ) located in the phenylacetamide moiety. Notably, this series was restricted only to three diastereoisomers (C1- R )-31 – 33 , which were analogues of the most potent anticonvulsants with the R -configuration reported previously [ 8 ]. Furthermore, as an amine function in position three of the pyrrolidine-2,5-dione, we introduced the dimethylamine moiety that appeared to be especially beneficial for anticonvulsant activity among compounds 13 – 18 .…”

“…Our most recent studies led to the identification of several hybrid compounds belonging to a group of pyrrolidine-2,5-dione derivatives, which proved to be promising candidates for further preclinical development in epilepsy and neuropathic pain indications [ 6 , 7 , 8 ]. It should be mentioned here that succinimide derivatives have been explored by many research groups in the CNS area, i.e., for the identification of new anticonvulsant and antidepressant agents [ 9 , 10 , 11 ].…”

“…Importantly, compound II ( R -enantiomer) vs. I (racemate) was characterized by a distinctly more beneficial safety profile in the rotarod test, a higher metabolic stability on human liver microsomes (HLMs), as well as a less pronounced inhibition of CYP2C9 [ 8 ]. Notably, both I and II (data not published till now for II) demonstrated a potent effectiveness by decreasing pain responses in the capsaicin-induced pain, the formalin-induced tonic pain, and the oxaliplatin (OXPT)-induced neuropathic pain models in mice [ 7 ].…”

“…Despite the beneficial pharmacological properties of I and II, as well as their close analogues described before [ 12 , 13 , 14 , 15 ], the main drawback of these molecules is the low water solubility, hampering the preparation of optimal oral formulations. To address this problem, we designed and synthesized herein a series of water-soluble hydrochlorides, which are obtained by the introduction of an amine moiety into pyrrolidine-2,5-dione ring of previously described anticonvulsants [ 6 , 7 , 8 ]. It should be stressed that such compounds with an improved water solubility may also facilitate the development of intravenous formulations used in emergency clinical conditions, e.g., status epilepticus.…”