Acyl dihydropyrazolo[1, 5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators. Issue 22 (15th November 2015)

• Record Type: Journal Article
• Authors: Malosh, Chrysa; Turlington, Mark; Bridges, Thomas M.; Rook, Jerri M.; Noetzel, Meredith J.; Vinson, Paige N.; Steckler, Thomas; Lavreysen, Hilde; Mackie, Claire; Bartolomé-Nebreda, José M.; Conde-Ceide, Susana; Martínez-Viturro, Carlos M.; Piedrafita, María; Sánchez-Casado, M. Rosa; Macdonald, Gregor J.; Daniels, J. Scott; Jones, Carrie K.; Niswender, Colleen M.; Conn, P. Jeffrey; Lindsley, Craig W.; Stauffer, Shaun R.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 22(2015)
• Page Start: 5115
• Page End: 5120
• Publication Date: 2015-11-15
• Subjects: Metabotropic glutamate receptor 5 (mGlu5) -- Positive allosteric modulator (PAM); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.10.009
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We report the optimization of a series of metabotropic glutamate receptor 5 (mGlu5 ) positive allosteric modulators (PAMs) from an acyl dihydropyrazolo[1, 5- a ]pyrimidinone class. Investigation of exocyclic amide transpositions with this unique 5, 6-bicyclic core were conducted in attempt to modulate physicochemical properties and identify a suitable backup candidate with a reduced half-life. A potent and selective PAM, 1-(2-(phenoxymethyl)-6, 7-dihydropyrazolo[1, 5- a ]pyrimidin-4(5 H )-yl)ethanone (9a, VU0462807), was identified with superior solubility and efficacy in the acute amphetamine-induced hyperlocomotion (AHL) rat model with a minimum effective dose of 3 mg/kg. Attempts to mitigate oxidative metabolism of the western phenoxy of9a through extensive modification and profiling are described.