Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 2: 4-Thiopyridyl acetophenones as non-tetrazole containing mGlu2 receptor potentiators

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 23; pp. 5867 - 5872
• Main Authors: Pinkerton, Anthony B., Cube, Rowena V., Hutchinson, John H., James, Joyce K., Gardner, Michael F., Schaffhauser, Hervé, Rowe, Blake A., Daggett, Lorrie P., Vernier, Jean-Michel
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 06.12.2004; Elsevier
• Subjects: Acetophenones - chemistry; Acetophenones - metabolism; Allosteric; Allosteric Regulation - physiology; Animals; Biological and medical sciences; Brain - metabolism; Cell Line; Glutamate receptors; Glutamatergic system (aspartate and other excitatory aminoacids); GPCRs; Humans; Medical sciences; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Protein Binding - physiology; Pyridines - chemistry; Pyridines - metabolism; Rats; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - metabolism; Schizophrenia; Structure-Activity Relationship; Tetrazoles; Glutamate receptors; Allosteric; Schizophrenia; GPCRs; Penetration; Structure activity relation; Allosteric regulation; Acetophenone derivatives; Central nervous system; In vitro; mglu2 glutamate receptor; Pyridine derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.09.028

We have identified and synthesized a series of 4-thiopyridyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure–activity relationship studies directed toward replacement of the tetrazole in the initial lead led to the discovery of 16 (EC 50 = 340 nM), which showed improved brain penetration over the initial lead. We have identified and synthesized a series of 4-thiopyridyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure–activity relationship studies directed toward replacement of the tetrazole in the initial lead led to the discovery of 16 (EC 50 = 340 nM), which showed improved brain penetration over the initial lead.