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.

Felts AS, Rodriguez AL, Morrison RD, Bollinger KA, Venable DF, Blobaum AL, Byers FW, Thompson Gray A, Daniels JS, Niswender CM, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
Bioorg Med Chem Lett. 2017 27 (21): 4858-4866

PMID: 28958625 · PMCID: PMC5716465 · DOI:10.1016/j.bmcl.2017.09.042

Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu 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 versus DAT.

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MeSH Terms (18)

Allosteric Regulation Amides Animals Cell Membrane Permeability Dogs Dopamine Plasma Membrane Transport Proteins Drug Evaluation, Preclinical Half-Life Humans Inhibitory Concentration 50 Madin Darby Canine Kidney Cells Mice Microsomes, Liver Pyridines Rats Receptor, Metabotropic Glutamate 5 Structure-Activity Relationship Triazoles

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