Acyl dihydropyrazolo[1,5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators.
Basic Information
ID: ALA3632544
Journal: Bioorg Med Chem Lett
Title: Acyl dihydropyrazolo[1,5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators.
Authors: Malosh C, Turlington M, Bridges TM, Rook JM, Noetzel MJ, Vinson PN, Steckler T, Lavreysen H, Mackie C, Bartolomé-Nebreda JM, Conde-Ceide S, Martínez-Viturro CM, Piedrafita M, Sánchez-Casado MR, Macdonald GJ, Daniels JS, Jones CK, Niswender CM, Conn PJ, Lindsley CW, Stauffer SR.
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(5H)-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 3mg/kg. Attempts to mitigate oxidative metabolism of the western phenoxy of 9a through extensive modification and profiling are described.
CiteXplore: 26475522
DOI: 10.1016/j.bmcl.2015.10.009
Patent ID: ┄