title: Design, synthesis, and development of novel caprolactam anticonvulsants.
abstract: Epilepsy afflicts 1-2% of the world's population and often goes untreated; nearly 70% of those with a form of epilepsy fail to receive proper treatment. Therefore, there is great demand for the design of novel, effective anticonvulsants to combat epilepsy in its numerous forms. Previously, alpha-hydroxy-alpha-phenylcaprolactam was found to have rather potent antiepileptic activity [anti-maximal electroshock (MES) ED(50)=63 mg/kg and anti-subcutaneous Metrazol (scMet) ED(50)=74 mg/kg] when administered intraperitoneally in mice. We focused our attention on the development of this compound through traditional medicinal chemistry techniques-including the Topliss approach, isosteric replacement, methylene insertion, and rigid analogue approach-in the hopes of determining the effect of caprolactam alpha-substitution and other structural modifications on anticonvulsant activity. A number of the desired targets were successfully synthesized and submitted to the Anticonvulsant Screening Program of the National Institute of Neurological Disorders and Stroke (NINDS). Phase I results were quite promising for at least three of the compounds: alpha-ethynyl-alpha-hydroxycaprolactam (10), alpha-benzyl-alpha-hydroxycaprolactam (11), and alpha-hydroxy-alpha-(phenylethynyl)caprolactam (13). Phase II results for 11 strongly suggested it as a new structural class for further development, as it exhibited an anti-MES T.I. in excess of 4.0. Further, the potent activity of 13 in all models also pointed to the substituted alkynylcaprolactams as a new anticonvulsant structural class.
authors.affiliation: Department of Chemistry, University of Virginia, McCormick Road, PO Box 400319, Charlottesville, VA 22904, USA.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Grimm
authors.forename: James P
authors.initials: JP
authors.lastname: Stables
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002209:Caprolactam / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D004827:Epilepsy / Q000188:drug therapy; D007274:Injections, Intraperitoneal; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D002209:Caprolactam