title: An approach to the design of novel cognitive enhancers using molecular modeling and X-ray crystallography.
abstract: A novel series of cognition enhancers was designed based on molecular modeling and X-ray structure analysis of EXP-9121 (2). This new series features a spirocyclic ring system that constrains the side chain substituents into the orientation seen in the X-ray crystal structure of 2. MM2 calculations preformed on 2 accurately predicted the solid state conformation. Compounds could be rapidly assembled using a bis-Michael addition reaction. Unfortunately, in vitro testing showed moderate activity at best, suggesting the X-ray structure of 2 does not mimic the bioactive conformation.
authors.affiliation: Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0353, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Nugiel
authors.forename: M E
authors.initials: ME
authors.lastname: Voss
authors.forename: D R
authors.initials: DR
authors.lastname: Brittelli
authors.forename: J C
authors.initials: JC
authors.lastname: Calabrese
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D008958:Models, Molecular; D008968:Molecular Conformation; D018697:Nootropic Agents / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats
chemical_list: D018697:Nootropic Agents; D011725:Pyridines; C094392:X 9121; D000109:Acetylcholine