Merging the Structural Motifs of Functionalized Amino Acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities

Abstract

Functional amino acids (FAAs) and α-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4′-((3″-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED 50 values of 13, 14, ~10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases.Epilepsy is a chronic disorder, characterized by recurrent, unprovoked seizures. 1 A seizure is defined as a discrete clinical event arising from transient, hypersynchronous, abnormal neuronal behavior. Epilepsy, then, is not a disease but rather a syndrome arising from a group of nonspecific, dysfunctional events in the brain. The treatment mainstay for patients with epileptic disorders has been the long-term and consistent administration of anticonvulsant drugs. 2,3 There are more than 40 pharmacologic therapies used for the treatment of epilepsy. 4 Unfortunately, even when used optimally, these therapeutic interventions are ineffective for some 30% of patients. 5 Moreover, their use is associated, in more than 40% of patients, with untoward effects (e.g., drowsiness, dizziness, nausea, liver damage). 6 The shortcomings of current regimens highlight the need for new, more effective agents.CORRESPONDING AUTHOR FOOTNOTE: Division of Medicinal Chemistry and Natural Products, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568 and Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599-3290, hkohn@email.unc.edu, Telephone: 919-843-8112, Fax: 919-966-0204. Supporting Information Available: Synthetic procedures for the intermediates leading to the preparation of 5,9, (R)-6-8, (R)-10-22, (S)-6, (S)-10, 74, and 75, elemental analyses, 1 H and 13 C NMR spectra of compounds 5, (R)-6-8, 9, (R)-10-22, (S)-6, (S)-10, 74, and 75 evaluated in this study. This material is available free of charge via the internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Med Chem. Author manuscript; available in PMC 2011 May 13. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWe have previously reported that functionalized amino acids (FAAs, a 1) [7][8][9][10][11][12][13][14][15][16][17][18] exhibit excellent anticonvulsant activities in various animal seizure models. ...

Identification of the Benzyloxyphenyl Pharmacophore: A Structural Unit That Promotes Sodium Channel Slow Inactivation

“…Thus, we tested (3-fluoro)benzyl phenyl ether (7), 4-((3′-fluoro)benzyloxy)benzylamine (8), 10 and N-4-((3′-fluoro)benzyloxy)benzyl acetamide (9). 10 These three compounds contain a substituted benzyloxyphenyl B group but are devoid of the adjacent amino acid unit.…”

“…Thus, we tested (3-fluoro)benzyl phenyl ether (7), 4-((3′-fluoro)benzyloxy)benzylamine (8), 10 and N-4-((3′-fluoro)benzyloxy)benzyl acetamide (9). 10 These three compounds contain a substituted benzyloxyphenyl B group but are devoid of the adjacent amino acid unit. We observed that the (3-fluoro)benzyloxyphenyl units in 7− 9 induced almost similar levels of maximal Na + channel slow inactivation ( Figure 7A, B) with maximal slow inactivation IC 50 values of 2.3 μM for 7, 10 μM for 8, and 11.9 μM for 9 (Table 1).…”

The Epilepsy Foundation's 4th Biennial Epilepsy Pipeline Update Conference

“…The plans for testing this compound in human clinical trials are underway. [22,24]. He noted that ENAs strategically combine pharmacophores found in functionalized amino acids (FAAs), such as lacosamide (Vimpat®), with α-aminoamides (AAAs), such as safinamide and ralfinamide.…”

Recent Progress in Anticonvulsant Drug Research: Strategies for Anticonvulsant Drug Development and Applications of Antiepileptic Drugs for Non-Epileptic Central Nervous System Disorders

“…Salomé et al [182] combined the pharmacophoric groups of these two classes in one structure to design a new series of potential anticonvulsant compounds expecting better activities than either LCA, a representative of prototypical FAA (41) or safinamide (SAF) (in Table 2), prototypical AAAs (42) in MES seizure model. In this article, they reported the reason of the design strategies, synthesis of compounds, and pharmacological evaluation of the compounds that fit the general structure of 43 consisting of group I, II, III.…”