Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5)
| Autor: | Andrew P. Marcus, Linda A. Sygowski, Reto Gadient, James B. Campbell, Dean G. Brown, Jeffrey G. Varnes, Megan M. King, Valerie Hoesch, Scott Throner, Russell C. Mauger, Xia Wang, Nathan Spear |
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| Rok vydání: | 2010 |
| Předmět: |
chemistry.chemical_classification
Ketone Metabotropic glutamate receptor 5 Stereochemistry Receptor Metabotropic Glutamate 5 Organic Chemistry Clinical Biochemistry Allosteric regulation Pharmaceutical Science Ligand (biochemistry) Receptors Metabotropic Glutamate Biochemistry Chemical synthesis chemistry.chemical_compound Inhibitory Concentration 50 chemistry Phenylacetylene Allosteric Regulation Drug Design Drug Discovery Lipophilicity Molecular Medicine Moiety Molecular Biology |
| Zdroj: | Bioorganicmedicinal chemistry letters. 21(5) |
| ISSN: | 1464-3405 |
| Popis: | Novel in vitro mGlu(5) positive allosteric modulators with good potency, solubility, and low lipophilicity are described. Compounds were identified which did not rely on the phenylacetylene and carbonyl functionalities previously observed to be required for in vitro activity. Investigation of the allosteric binding requirements of a series of dihydroquinolinone analogs led to phenylacetylene azachromanone 4 (EC(50) 11.5 nM). Because of risks associated with potential metabolic and toxicological liabilities of the phenylacetylene, this moiety was successfully replaced with a phenoxymethyl group (27; EC(50) 156.3 nM). Derivation of a second-generation of mGlu(5) PAMs lacking a ketone carbonyl resulted in azaindoline (33), azabenzimidazole (36), and N-methyl 8-azaoxazine (39) phenylacetylenes. By scoping nitrogen substituents and phenylacetylene replacements in 39, we identified phenoxymethyl 8-azaoxazine 47 (EC(50) 50.1 nM) as a potent and soluble mGlu(5) PAM devoid of both undesirable phenylacetylene and carbonyl functionalities. |
| Databáze: | OpenAIRE |
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