1384262-83-2Relevant academic research and scientific papers
Tetrahydronaphthyridine and dihydronaphthyridinone ethers as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu 5)
Turlington, Mark,Malosh, Chrysa,Jacobs, Jon,Manka, Jason T.,Noetzel, Meredith J.,Vinson, Paige N.,Jadhav, Satyawan,Herman, Elizabeth J.,Lavreysen, Hilde,Mackie, Claire,Bartolomé-Nebreda, José M.,Conde-Ceide, Susana,Martín-Martín, M. Luz,Tong, Han Min,López, Silvia,Macdonald, Gregor J.,Steckler, Thomas,Daniels, J. Scott,Weaver, C. David,Niswender, Colleen M.,Jones, Carrie K.,Conn, P. Jeffrey,Lindsley, Craig W.,Stauffer, Shaun R.
, p. 5620 - 5637 (2014/08/05)
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure-activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.
NAPHTHYRIDINONE ANALOGS AS MGLUR5 POSITIVE ALLOSTERIC MODULATORS
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, (2012/07/14)
In one aspect, the invention relates to naphthyridinone analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
