1. Synthesis and anticonvulsant activities of (R)-N-(4'-substituted)benzyl 2-acetamido-3-methoxypropionamides
Erica DeMarco, Robert Swendiman, Elise Salomé-Grosjean, James P Stables, Ki Duk Park, Christophe Salomé, Pierre Morieux, Harold Kohn J Med Chem . 2010 Feb 11;53(3):1288-305. doi: 10.1021/jm901563p.
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 nonbulky 4'-substituted (R)-3 derivatives exhibited superb activity, independent of their electronic properties. Activities in the MES test of several compounds were comparable with or exceeded that of (R)-3 and surpassed the activities observed for the traditional antiepileptic agents phenytoin, phenobarbital, and valproate.
2. Synthesis of glycopeptides containing the amino acid sequence 17-23 of bovine pancreatic deoxyribonuclease
H G Garg, R W Jeanloz Carbohydr Res . 1980 Nov 1;86(1):59-68. doi: 10.1016/s0008-6215(00)84581-4.
2-Acetamido-3,4,6-tri-O-acetyl-1-N-[N-(benzyloxycarbonyl-L- seryl)-L-aspart-1-oyl-(p-nitrobenzyl ester)-4-oyl]-2-deoxy-beta-D-glucopyranosylamine, 2-acetamido-3,4,6-tri-O-acetyl-1-N-[N-(benzyloxycarbonyl-L-seryl)-L-aspart-1-oy l-(L-alanine methyl ester)-4-oyl]-2-deoxy-beta-D-glucopyranosylamine, and 2-acetamido-3,4,6-tri-O-acetyl-1-N-[N-benzyloxycarbonyl)-L-aspart-1-oyl-(L-alan yl-L-threonyl-L-leucyl-L-alanyl-L-serine p-nitrobenzyl ester)-4-oyl]-2-deoxy-beta-D-glucopyranosylamine (7), which span the amino acid sequence 17-23 of bovine pancreatic deoxyribonuclease A and contain a 2-acetamido-2-deoxy-D-glucose residue, were synthesized. On treatment with lithium hydroxide, the blocked glycohexapeptide 7 gave 2-acetamido-1-N-[N-(benzyloxycarbonyl)-L-aspart-1-oyl-(L-alanyl-L-threonyl-L-le ucyl-L-analyl-L-serine)-4-oyl]-2-deoxy-beta-D-glucopyranosylamine.
3. Substituted N-(biphenyl-4'-yl)methyl (R)-2-acetamido-3-methoxypropionamides: potent anticonvulsants that affect frequency (use) dependence and slow inactivation of sodium channels
Robert Torregrosa, Yuying Wang, Cindy Barbosa, Sarah M Wilson, Ki Duk Park, Yucheng Xiao, Rajesh Khanna, Erik T Dustrude, Theodore R Cummins, Xiao-Fang Yang, Harold Kohn, Hyosung Lee J Med Chem . 2014 Jul 24;57(14):6165-82. doi: 10.1021/jm500707r.
We prepared 13 derivatives of N-(biphenyl-4'-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound's whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI=TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.
