Discovery of Novel Central Nervous System Penetrant Metabotropic Glutamate Receptor Subtype 2 (mGlu 2 ) Negative Allosteric Modulators (NAMs) Based on Functionalized Pyrazolo[1,5- a]pyrimidine-5-carboxamide and Thieno[3,2- b]pyridine-5-carboxamide Cores

Elizabeth S. Childress, Joshua M. Wieting, Andrew S. Felts, Megan M. Breiner, Madeline F. Long, Vincent B. Luscombe, Alice L. Rodriguez, Hyekyung P. Cho, Anna L. Blobaum, Colleen M. Niswender, Kyle A. Emmitte, P. Jeffrey Conn, Craig W. Lindsley

Research output: Contribution to journalArticle

3 Scopus citations


A scaffold hopping exercise from a monocyclic mGlu 2 NAM with poor rodent PK led to two novel heterobicyclic series of mGlu 2 NAMs based on either a functionalized pyrazolo[1,5-a]pyrimidine-5-carboxamide core or a thieno[3,2-b]pyridine-5-carboxamide core. These novel analogues possess enhanced rodent PK, while also maintaining good mGlu 2 NAM potency, selectivity (versus mGlu 3 and the remaining six mGlu receptors), and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.

Original languageEnglish
Pages (from-to)378-384
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number1
StatePublished - 1 Oct 2019


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