Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10591169 | Bioorganic & Medicinal Chemistry Letters | 2014 | 6 Pages |
Abstract
We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (11, VU0462054), bearing a simple ketone moiety, was identified (LEÂ =Â 0.52, LELPÂ =Â 3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series.
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Authors
Mark Turlington, Meredith J. Noetzel, Thomas M. Bridges, Paige N. Vinson, Thomas Steckler, Hilde Lavreysen, Claire Mackie, José M. Bartolomé-Nebreda, Susana Conde-Ceide, Han Min Tong, Gregor J. Macdonald, J. Scott Daniels, Carrie K. Jones,