Syntheses and evaluation of anticonvulsant profile and teratogenicity of novel amide derivatives of branched aliphatic carboxylic acids with 4-aminobenzensulfonamide

J Med Chem. 2010 May 27;53(10):4177-86. doi: 10.1021/jm100170w.

Abstract

Despite the availability of 14 new antiepileptic drugs (AEDs), about 30% of epileptic patients are not seizure-free. Consequently there is substantial need to develop new effective AEDs. A novel class of aromatic amides composed of phenylacetic acid or branched aliphatic carboxylic acids, with five to nine carbons in their carboxylic moiety, and aminobenzenesulfonamide were synthesized and evaluated in the anticonvulsant rat-maximal electroshock (MES) and subcutaneous metrazol seizure (scMet) tests. Fourteen of the synthesized amides had an anticonvulsant ED(50) of <50 mg/kg in the rat-MES test. The amides 2-methyl-N-(4-sulfamoylphenyl)butyramide (10), 2-ethyl-N-(4-sulfamoylphenyl)butyramide (11), and 3,3-dimethyl-N-(4-sulfamoylphenyl)butyramide (15) were the most potent compounds possessing MES-ED(50) values of 7.6, 9.9, and 9.4 mg/kg and remarkable protective index (PI = TD(50)/ED(50)) values of 65.7, 50.5, and 53.2, respectively. These potent sulfanylamides caused neural tube defects only at doses markedly exceeding their effective dose. The anticonvulsant properties of these compounds make them potential candidates for further development as new, potent, and safe AEDs.

MeSH terms

  • Anilides / chemical synthesis*
  • Anilides / pharmacology
  • Anilides / toxicity
  • Animals
  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / pharmacology
  • Anticonvulsants / toxicity
  • Convulsants
  • Electroshock
  • Mice
  • Neural Tube Defects / chemically induced*
  • Pentylenetetrazole
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / drug therapy*
  • Seizures / etiology
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacology
  • Sulfonamides / toxicity

Substances

  • 2-ethyl-N-(4-sulfamoylphenyl)butyramide
  • 2-methyl-N-(4-sulfamoylphenyl)butyramide
  • 3,3-dimethyl-N-(4-sulfamoylphenyl)butyramide
  • Anilides
  • Anticonvulsants
  • Convulsants
  • Sulfonamides
  • Pentylenetetrazole