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ID: ALA3351812
Journal: Bioorg Med Chem Lett
Title: Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency.
Authors: Turlington M, Noetzel MJ, Bridges TM, Vinson PN, Steckler T, Lavreysen H, Mackie C, Bartolomé-Nebreda JM, Conde-Ceide S, Tong HM, Macdonald GJ, Daniels JS, Jones CK, Niswender CM, Conn PJ, Lindsley CW, Stauffer SR.
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 (LE=0.52, LELP=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.
CiteXplore: 24961642