Acyl dihydropyrazolo[1,5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Malosh, Chrysa^1,2,3,4  Turlington, Mark^1,2,3,4  Bridges, Thomas M.^1,2,3  Rook, Jerri M.^1,2,3  Noetzel, Meredith J.^1,2,3  Vinson, Paige N.^1,2,3  Steckler, Thomas⁵  Lavreysen, Hilde⁵  Mackie, Claire⁶  Bartolome-Nebreda, Jose M.⁷  Conde-Ceide, Susana⁷  Martinez-Viturro, Carlos M.⁷  Piedrafita, Maria⁷  Sanchez-Casado, M. Rosa⁷  Macdonald, Gregor J.⁵  Daniels, J. Scott^1,2,3  Jones, Carrie K.^1,2,3  Niswender, Colleen M.^1,2,3  Conn, P. Jeffrey^1,2,3  Lindsley, Craig W.^1,2,3,4  Stauffer, Shaun R.^1,2,3,4 

[1] Vanderbilt Univ, Dept Pharmacol, Med Ctr, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Vanderbilt Ctr Neurosci Drug Discovery, Med Ctr, Nashville, TN 37232 USA

[3] Vanderbilt Specialized Chem Ctr Probe Dev MLPCN, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[5] Janssen Res & Dev, Neurosci, B-2340 Beerse, Belgium

[6] Janssen Res & Dev, Discovery Sci ADME Tox, Toledo 45007, Spain

[7] Janssen Res & Dev, Neurosci Med Chem, Toledo 45007, Spain

关键词: Metabotropic glutamate receptor 5 (mGlu(5));    Positive allosteric modulator (PAM);   

DOI  :  10.1016/j.bmcl.2015.10.009

来源: Elsevier

【 摘 要 】

We report the optimization of a series of metabotropic glutamate receptor 5 (mGlu(5)) 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 3 mg/kg. Attempts to mitigate oxidative metabolism of the western phenoxy of 9a through extensive modification and profiling are described. (C) 2015 Elsevier Ltd. All rights reserved.

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