Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo [1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

作者：Felts Andrew S; Rodriguez Alice L; Morrison Ryan D; Bollinger Katrina A; Venable Daryl F; Blobaum Anna L; Byers Frank W; Gray Analisa Thompson; Daniels J Scott; Niswender Colleen M; Jones Carrie K; Conn P Jeffrey; Lindsley Craig W; Emmitte Kyle A^*

来源：Bioorganic & Medicinal Chemistry Letters, 2017, 27(21): 4858-4866.

DOI：10.1016/j.bmcl.2017.09.042

• Metabotropic glutamate receptor subtype 5 (mGlu5)
• Negative allosteric modulator (NAM)
• Central nervous system (CNS)
• G-protein coupled receptor (GPCR)
• Heterocycle

Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu(5) NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu(5) NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu(5) versus DAT.

• 出版日期2017-11-1