Synthesis and Anticonvulsant Activities of (R)-N-(4′-Substituted)benzyl 2-Acetamido-3-methoxypropionamides

Abstract

The structure-activity relationship (SAR) for the N-benzyl group in the clinical antiepileptic agent (R)-lacosamide ((R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-3) has been explored. Forty-three compounds were prepared and then evaluated at the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program for seizure protection in the maximal electroshock (MES) and subcutaneous Metrazol models. Comparing activities for two series of substituted aryl regioisomers (2′, 3′, 4′) showed that 4′-modified derivatives had the highest activity. Significantly, structural latitude existed at the 4′-site. The SAR indicated that non-bulky 4′-substituted (R)-3 derivatives exhibited superb activity, independent of their electronic properties. Activities in the MES test of several compounds were either comparable with or exceeded that of (R)-3, and surpassed the activities observed for the traditional antiepileptic agents phenytoin, phenobarbital, and valproate.Epilepsy, a major neurological disorder that affects all populations, 1 describes the types of recurrent seizures produced by paroxysmal, excessive, synchronous neuronal discharges in the brain. 2,3 In the United States alone, over 2 million people suffer from epilepsy and its sequelae; 340,000 are children. 4 For many of these individuals, the disabilities and associated neuropsychological and behavioral factors adversely affect their quality of life. The lifestyle restrictions plus the large expense for treatment, lost productivity, and rehabilitation result in a huge cost to society. 4 The treatment mainstay for patients with epileptic disorders has been the long-term and consistent administration of anticonvulsant drugs. 5,6 Unfortunately, current medications are ineffective for approximately one-third of these patients. 7 Many continue to have seizures, while others experience disturbing side effects (e.g., drowsiness, dizziness, nausea, liver damage). 8 Thus, there is a need for more efficacious drugs that function by different pharmacological pathways.CORRESPONDING AUTHOR: 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 number: 919-966-0204. Supporting Information Available: Synthetic procedures for the intermediates leading to the preparation of (R)-4, 7-31, 33-39, 60, and 61, and (S)-11, 21, 23, 26, 28, 29, 34, and 38, elemental analyses, 1 H and 13 C NMR spectra of compounds 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 February 11. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn 1985, we discovered a novel class of anticonvulsant agents, termed functionalized amino acids (FAA, a 1). ...

Design, Synthesis, and Anticonvulsant Activity of New Hybrid Compounds Derived from 2-(2,5-Dioxopyrrolidin-1-yl)propanamides and 2-(2,5-Dioxopyrrolidin-1-yl)butanamides

“…at the fixed dose of 300 mg/kg, and the anticonvulsant protection was observed at four pretreatment times-0.25, 0.5, 1 and 2 h. The method applied here allowed the determination of the number of animals (in a group consisting of four mice) protected against electrically induced seizures as well as the estimation of the time course of anticonvulsant activity together with time of peak effect (TPE). The protection profiles for 2-(2,5-dioxopyrrolidin-1-yl)propanamides (3-15, 30) and 2-(2,5-dioxopyrrolidin-1-yl)butanamides (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) are shown in Table 1.…”

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.…”

Chimeric derivatives of functionalized amino acids and α-aminoamides: Compounds with anticonvulsant activity in seizure models and inhibitory actions on central, peripheral, and cardiac isoforms of voltage-gated sodium channels

“…Similarly, we found no activity in the scMet model for ( R )- 1 11 and structurally related compounds. 8–10,36 …”