Bicyclo((aryl)methyl)benzamides as inhibitors of GlyT1
| Autor: | Gaochao Tian, William Frietze, Michael W. Wood, Christopher R. Holmquist, Todd Andrew Brugel, William E. Palmer, Hui Xiong, Deidre E. Wilkins, Glen Ernst, William Potts, Lindsay Hinkley, Janet Marie Forst, Xia Wang, Jeffrey S. Albert, Cristobal Alhambra, Gary Steelman, Jeffrey G. Varnes, Gerald Jonak, Don Andisik, Bruce Dembofsky, Chris Allan Veale |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
Stereochemistry Clinical Biochemistry Heteroatom Administration Oral Pharmaceutical Science 010402 general chemistry 01 natural sciences Biochemistry Rats Sprague-Dawley Bridged Bicyclo Compounds Mice Structure-Activity Relationship chemistry.chemical_compound Glycine Plasma Membrane Transport Proteins Drug Discovery Animals Humans Potency Benzamide Molecular Biology Dose-Response Relationship Drug Molecular Structure Bicyclic molecule 010405 organic chemistry Aryl Organic Chemistry Rats 0104 chemical sciences Ring size chemistry Benzamides Injections Intravenous Lipophilicity Glycine Molecular Medicine Locomotion |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 28:1043-1049 |
| ISSN: | 0960-894X |
| Popis: | A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40–41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 μmol/kg compared to control. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect