KA‐104, a new multitargeted anticonvulsant with potent antinociceptive activity in preclinical models

Abstract

Objective: The main objective of the present work was to assess the utility of KA-104 as potential therapy for drug-resistant seizures and neuropathic pain, and to characterize its druglike properties in a series of absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) studies. We also aimed to establish its mechanism of action in electrophysiological studies. Methods: The activity of KA-104 against drug-resistant seizures was tested in the mouse 6-Hz (44-mA) model, whereas the antinociceptive activity was assessed with the capsaicin-and oxaliplatin-induced pain models in mice. The patch-clamp technique was used to study the influence of KA-104 on fast voltage-gated sodium currents in rat prefrontal cortex pyramidal neurons. The pharmacokinetic profile was determined after intraperitoneal (ip) injection in mice. The in vitro ADME-Tox properties were studied by applying routine testing procedures. Results: KA-104 was effective in the 6-Hz (44-mA) model (median effective dose [ED 50 ] = 73.2 mg/kg) and revealed high efficacy in capsaicin-induced neurogenic pain as well as in oxaliplatin-induced neuropathic pain in mice. Patch-clamp technique showed that KA-104 reversibly inhibits voltage-gated sodium currents. KA-104 was rapidly absorbed after the ip injection and showed relatively good penetration through the blood-brain barrier. This molecule was also characterized by high passive permeability, moderate influence on CYP2C9, and negligible hepatotoxicity on HepG2 cells. Significance: The results reported herein indicate that KA-104 is a new wide-spectrum multitargeted anticonvulsant with favorable in vitro ADME-Tox properties. Importantly, this compound may also prove to become an interesting and hopefully more effective therapeutic option for treatment of neuropathic pain.

The Search for New Anticonvulsants in a Group of (2,5-Dioxopyrrolidin-1-yl)(phenyl)Acetamides with Hybrid Structure—Synthesis and In Vivo/In Vitro Studies

“…In general, pyrrolidine-2,5-dione derivatives displayed satisfied stability as their conversion into metabolites was lower than 30% during 120 min incubation with HLMs. These results correlate with our previous studies, where high metabolic stability within this chemical group was also found [9,12,14,15,37]. Compound 4 showed the highest susceptibility for enzymatic biotransformations (71.4% of parent compound remained in the reaction mixture; see Figure S1, Supplementary Materials), resulting in double-hydroxylations (M1), pyrrolidine-2,5-dione ring hydrolysis (M2), or monohydroxylation (M3) as the most probable metabolic pathways (Figures S2 and S7, Supplementary Materials).…”

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

“…The higher acute neurotoxicity (motor impairment) in the rotarod test may result from very a fast penetration to the murine brain and a much higher concentration of salts in the CNS compared to the parent and hardly water-soluble compounds as it was observed for compound 14 and its direct analogue I (see compound KA-104, ref. [ 7 ]), in the pharmacokinetic studies (pharmacokinetic data for compound 14 are shown below).…”

“…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 ].…”

“…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.…”