1197983-10-0Relevant academic research and scientific papers
Primary amino acid derivatives: Substitution of the 4′-N′- benzylamide site in (R)-N′-benzyl 2-amino-3-methylbutanamide, (R)-N′-benzyl 2-amino-3,3-dimethylbutanamide, and (R)-N′-benzyl 2-amino-3-methoxypropionamide provides potent anticonvulsants with pain-attenuating properties
King, Amber M.,Salomé, Christophe,Salomé-Grosjean, Elise,De Ryck, Marc,Kaminski, Rafal,Valade, Anne,Stables, James P.,Kohn, Harold
supporting information; experimental part, p. 6417 - 6431 (2011/12/15)
Recently, we reported that select N′-benzyl 2-substituted 2-amino acetamides (primary amino acid derivatives (PAADs)) exhibited pronounced activities in established whole animal anticonvulsant (i.e., maximal electroshock seizure (MES)) and neuropathic pain (i.e., formalin) models. The anticonvulsant activities of C(2)-hydrocarbon N′-benzyl 2-amino acetamides (MES ED50 = 13-21 mg/kg) exceeded those of phenobarbital (ED 50 = 22 mg/kg). Two additional studies defining the structure-activity relationship of PAADs are presented in this issue of the journal. In this study, we demonstrated that the anticonvulsant activities of (R)-N′-benzyl 2-amino-3-methylbutanamide and (R)-N′-benzyl 2-amino-3,3-dimethylbutanamide were sensitive to substituents at the 4′-N′-benzylamide site; electron-withdrawing groups retained activity, electron-donating groups led to a loss of activity, and incorporating either a 3-fluorobenzyloxy or 3-fluorophenoxymethyl group using a rationally designed multiple ligand approach improved activity. Additionally, we showed that substituents at the 4′-N′-benzylamide site of (R)-N′-benzyl 2-amino-3-methoxypropionamide also improved anticonvulsant activity, with the 3-fluorophenoxymethyl group providing the largest (～4-fold) increase in activity (ED50 = 8.9 mg/kg), a value that surpassed phenytoin (ED50 = 9.5 mg/kg). Collectively, the pharmacological findings provided new information that C(2)-hydrocarbon PAADs represent a novel class of anticonvulsants.
Merging the structural motifs of functionalized amino acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities
Salomé, Christophe,Salomé-Grosjean, Elise,Stables, James P.,Kohn, Harold
supporting information; experimental part, p. 3756 - 3771 (2010/07/16)
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 ED50 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.
