Abstract
We report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (MES) test, the pentylenetetrazole-induced seizure model (scPTZ), and the psychomotor 6 Hz (32 mA) seizure model in mice. Compound 14 showed the most robust anticonvulsant activity (ED50 MES = 49.6 mg/kg, ED50 6 Hz (32 mA) = 31.3 mg/kg, ED50 scPTZ = 67.4 mg/kg). Notably, it was also effective in the 6 Hz (44 mA) model of drug-resistant epilepsy (ED50 = 63.2 mg/kg). Apart from favorable anticonvulsant properties, compound 14 revealed a high efficacy against pain responses in the formalin-induced tonic pain, the capsaicin-induced neurogenic pain, as well as in the oxaliplatin-induced neuropathic pain in mice. Moreover, compound 14 showed distinct anti-inflammatory activity in the model of carrageenan-induced aseptic inflammation. The mechanism of action of compound 14 is likely complex and may result from the inhibition of peripheral and central sodium and calcium currents, as well as the TRPV1 receptor antagonism as observed in the in vitro studies. This lead compound also revealed beneficial in vitro ADME-Tox properties and an in vivo pharmacokinetic profile, making it a potential candidate for future preclinical development. Interestingly, the in vitro studies also showed a favorable induction effect of compound 14 on the viability of neuroblastoma SH-SY5Y cells.
Highlights
Water solubility is one of the essential physicochemical properties from the perspective of formulation development for orally or parenterally administrated drug candidates [1]
The 13–18 were prepared according to the method depicted in Scheme 1
The N-(tert-butoxycarbonyl)-DL-phenylglycine was coupled in the presence of DCC (N,N 0 -dicyclohexylcarbodiimide) with an appropriate phenylpiperazine to give Boc-protected phenylglycine derivatives 1–3
Summary
Water solubility is one of the essential physicochemical properties from the perspective of formulation development for orally or parenterally (especially intravenously) administrated drug candidates [1]. It is a key driver for drug absorption, achieving a desired therapeutic exposure in plasma and target issues required for an effective pharmacological response. Bearing in mind the aforementioned facts, one of the important directions of lead compound optimization involves the improvement of its water solubility, which may be achieved by both physical and chemical methods. The physical approaches involve, among others, crystal engineering, particle size reduction, solid dispersion, the addition of surfactants, complexation, etc. [5]
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