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 Allen Emmitte, P. Jeffrey Conn, Craig W. Lindsley

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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
Volume62
Issue number1
DOIs
StatePublished - 1 Oct 2019

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Rodentia
Central Nervous System
pyridine
pyrazolo(1,5-a)pyrimidine
metabotropic glutamate receptor 2

Cite this

Childress, Elizabeth S. ; Wieting, Joshua M. ; Felts, Andrew S. ; Breiner, Megan M. ; Long, Madeline F. ; Luscombe, Vincent B. ; Rodriguez, Alice L. ; Cho, Hyekyung P. ; Blobaum, Anna L. ; Niswender, Colleen M. ; Emmitte, Kyle Allen ; Conn, P. Jeffrey ; Lindsley, Craig W. / 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 In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 1. pp. 378-384.
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abstract = "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.",
author = "Childress, {Elizabeth S.} and Wieting, {Joshua M.} and Felts, {Andrew S.} and Breiner, {Megan M.} and Long, {Madeline F.} and Luscombe, {Vincent B.} and Rodriguez, {Alice L.} and Cho, {Hyekyung P.} and Blobaum, {Anna L.} and Niswender, {Colleen M.} and Emmitte, {Kyle Allen} and Conn, {P. Jeffrey} and Lindsley, {Craig W.}",
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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 . / Childress, Elizabeth S.; Wieting, Joshua M.; Felts, Andrew S.; Breiner, Megan M.; Long, Madeline F.; Luscombe, Vincent B.; Rodriguez, Alice L.; Cho, Hyekyung P.; Blobaum, Anna L.; Niswender, Colleen M.; Emmitte, Kyle Allen; Conn, P. Jeffrey; Lindsley, Craig W.

In: Journal of Medicinal Chemistry, Vol. 62, No. 1, 01.10.2019, p. 378-384.

Research output: Contribution to journalArticleResearchpeer-review

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