Discovery of molecular switches within the ADX-47273 mGlu₅ PAM scaffold that modulate modes of pharmacology to afford potent mGlu₅ NAMs, PAMs and partial antagonists

This Letter describes a chemical lead optimization campaign directed at a weak mGlu₅ NAM discovered while developing SAR for the mGlu₅ PAM, ADX-47273. An iterative parallel synthesis effort discovered multiple, subtle molecular switches that afford potent mGlu₅ NAMs, mGlu₅ PAMs as well as mGlu₅ part...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-05, Vol.21 (9), p.2711-2714
Hauptverfasser:	Lamb, Jeffrey P, Engers, Darren W, Niswender, Colleen M, Rodriguez, Alice L, Venable, Daryl F, Conn, P. Jeffrey, Lindsley, Craig W
Format:	Artikel
Sprache:	eng
Schlagworte:	Allosteric Regulation antagonists Biological and medical sciences Drug Discovery Glutamatergic system (aspartate and other excitatory aminoacids) Medical sciences Molecular Structure Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Oxadiazoles - chemical synthesis Oxadiazoles - chemistry Oxadiazoles - pharmacology pharmacology Pharmacology. Drug treatments Piperidines - chemical synthesis Piperidines - chemistry Piperidines - pharmacology Protein Binding Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate - antagonists & inhibitors Stereoisomerism Structure-Activity Relationship structure-activity relationships
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Beschreibung
Zusammenfassung:	This Letter describes a chemical lead optimization campaign directed at a weak mGlu₅ NAM discovered while developing SAR for the mGlu₅ PAM, ADX-47273. An iterative parallel synthesis effort discovered multiple, subtle molecular switches that afford potent mGlu₅ NAMs, mGlu₅ PAMs as well as mGlu₅ partial antagonists.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.11.119