Stereoselective Synthesis of New (2S,3R)-3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid Analogues Utilizing a C(sp3)–H Activation Strategy and Structure–Activity Relationship Studies at the Ionotropic Glutamate Receptors
| Autor: | Jacob C. Hansen, Silke Kayser, Kasper B. Hansen, Stylianos Iliadis, Niels Krogsgaard-Larsen, Lennart Bunch, Darryl S. Pickering, Jed T. Syrenne, Markus Staudt, Piero Temperini, Younes Larsen, Birgitte Nielsen, Feng Yi, Aleksandra Moroz |
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| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences Physiology Chemistry Stereochemistry Cognitive Neuroscience Carboxylic acid Enantioselective synthesis Glutamate receptor Cell Biology General Medicine Biochemistry Pyrrolidine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine NMDA receptor Structure–activity relationship Stereoselectivity 030217 neurology & neurosurgery 030304 developmental biology Ionotropic effect |
| Zdroj: | ACS Chemical Neuroscience. 11:674-701 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.0c00003 |
| Popis: | Competitive antagonists for ionotropic glutamate receptors (iGluRs) are highly valuable tool compounds for studying health and disease states in the central nervous system. However, only few subtype selective tool compounds are available and the discovery of antagonists with novel iGluR subtype selectivity profiles remains a profound challenge. In this paper, we report an elaborate structure–activity relationship (SAR) study of the parental scaffold 2,3-trans-3-carboxy-3-phenyl-proline by the synthesis of 40 new analogues. Three synthetic strategies were employed with two new strategies of which one being a highly efficient and fully enantioselective strategy based on C(sp3)–H activation methodology. The SAR study led to the conclusion that selectivity for the NMDA receptors was a general trend when adding substituents in the 5′-position. Selective NMDA receptor antagonists were obtained with high potency (IC50 values as low as 200 nM) and 3–34-fold preference for GluN1/GluN2A over GluN1/GluN2B-D NMDA rec... |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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