Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency

作者：Turlington Mark; Noetzel Meredith J; Bridges Thomas M; Vinson Paige N; Steckler Thomas; Lavreysen Hilde; Mackie Claire; Bartolome Nebreda Jose M; Conde Ceide Susana; Tong Han Min; Macdonald Gregor J; Daniels J Scott; Jones Carrie K; Niswender Colleen M; Conn P Jeffrey; Lindsley Craig W; Stauffer Shaun R^*

来源：Bioorganic & Medicinal Chemistry Letters, 2014, 24(15): 3641-3646.

DOI：10.1016/j.bmcl.2014.04.087

• Metabotropic glutamate receptor 5 (mGlu(5))
• Positive allosteric modulator (PAM)

We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu(5)) 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.

• 出版日期2014-8-1