A nonmetabolized analog of phenytoin

• Published in: Journal of medicinal chemistry 1981-07, Vol.24 (7), p.843-847
• Main Authors: Henderson, James D, Dayton, Peter G, Israili, Zafar H, Mandell, Leon
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - chemical synthesis; Half-Life; Phenytoin - analogs & derivatives; Phenytoin - chemical synthesis; Phenytoin - metabolism; Rats; Time Factors; Tissue Distribution
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00139a015

Nine novel analogues of 5,5-diphenylhydantoin bearing a CF3 group(s) in the meta or para position of one or both rings were synthesized. Preliminary evaluation of all the analogues (performed by the ADD Program, NIH) indicated no significant anticonvulsant activity against electrical or chemical shock in mice at doses of less than or equal to 100 mg/kg. The analogue 5,5-bis[4-(trifluoromethyl)phenyl]hydantoin (1) was synthesized labeled with 14C in the 4 position of the hydantoin ring. Certain physicochemical properties (pKa, partition ratio, protein binding, etc.) and the LD50 of 1 in mice (40 mg/kg, ip; 100 mg/kg, po) were determined. The disposition of [14C]1 was determined in rodents. The compound was excreted unchanged in rat feces (94% in 18 days), urinary excretion less than 0.5%. The half-life of elimination of [14C]1 from plasma was 67-72 h (ip and iv) in rats and 115 h (ip) in mice. Studies of tissue distribution and biliary excretion of [14C]1 indicate low tissue/plasma ratios (due to high plasma binding, 97%) and low biliary excretion. The lack of metabolism of [14C]1 may possibly be explained by (1) the strong electron-withdrawing effects of CF3 substituents, (2) the preemption of the primary metabolic sites, (3) the accompanying steric hindrance, and (4) the apparent inability of the CF3 group to undergo the NIH shift.