An approach to the design of novel cognitive enhancers using molecular modeling and X-ray crystallography.
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.
Nugiel
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DA
Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0353, USA.
Voss
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ME
Brittelli
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DR
Calabrese
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JC
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
D018697:Nootropic Agents; D011725:Pyridines; C094392:X 9121; D000109:Acetylcholine