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

• Published in: Journal of medicinal chemistry 2011-10, Vol.54 (19), p.6417-6431
• Main Authors: King, Amber M, Salomé, Christophe, Salomé-Grosjean, Elise, De Ryck, Marc, Kaminski, Rafal, Valade, Anne, Stables, James P, Kohn, Harold
• Format: Article
• Language: English
• Subjects: Amino Acids - chemical synthesis; Amino Acids - chemistry; Amino Acids - pharmacology; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Butyrates - chemical synthesis; Butyrates - chemistry; Butyrates - pharmacology; Male; Mice; Neuralgia - drug therapy; Neuralgia - physiopathology; Pain Measurement; Propionates - chemical synthesis; Propionates - chemistry; Propionates - pharmacology; Rats; Rats, Sprague-Dawley; Seizures - drug therapy; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200759t

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 (ED50 = 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.