title: Optimized synthesis of AMPA receptor antagonist ZK 187638 and neurobehavioral activity in a mouse model of neuronal ceroid lipofuscinosis.
abstract: Previous structure-activity relationship studies in the search for a potent, noncompetitive alpha-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist led to 2,3-dimethyl-6-phenyl-12H-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine (ZK 187638). However, the first synthesis had some drawbacks regarding reagents, processes, and overall yield, which furthermore decreased when the synthesis was scaled up. Therefore, we now report a new synthetic route for this compound which requires fewer steps and is suited for large-scale production. This compound significantly relieved the symptoms of neuromuscular deficit in mnd mice, a model of neuronal ceroid lipofuscinosis with motor neuron dysfunction. After oral administration, the concentrations of the compound in the brain and spinal cord were about threefold higher than those in the plasma. In summary, this novel AMPA antagonist is accessible through an optimized synthetic route, has good neurobehavioral activity, oral bioavailability, and favorable brain penetration. This opens new possibilities for the treatment of devastating neurological diseases that are mediated by the AMPA receptor.
authors.affiliation: Schering AG, Muellerstrasse 178, Berlin, Germany. bernd.elger@schering.de
authors.forename: Bernd
authors.initials: B
authors.lastname: Elger
authors.forename: Matthias
authors.initials: M
authors.lastname: Schneider
authors.forename: Eric
authors.initials: E
authors.lastname: Winter
authors.forename: Lucia
authors.initials: L
authors.lastname: Carvelli
authors.forename: Marco
authors.initials: M
authors.lastname: Bonomi
authors.forename: Claudia
authors.initials: C
authors.lastname: Fracasso
authors.forename: Giovanna
authors.initials: G
authors.lastname: Guiso
authors.forename: Milena
authors.initials: M
authors.lastname: Colovic
authors.forename: Silvio
authors.initials: S
authors.lastname: Caccia
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use*; D002490:Central Nervous System / Q000187:drug effects; D004149:Dioxoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D015394:Molecular Structure; D009048:Motor Skills / Q000187:drug effects*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000503:physiopathology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*
chemical_list: C502816:2,3-dimethyl-6-phenyl-12H-(1,3)dioxolo(4,5-h)imidazo(1,2-c)(2,3)benzodiazepine; D004149:Dioxoles; D018091:Receptors, AMPA; D001569:Benzodiazepines