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

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

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu5 NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu5 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 mGlu5 versus DAT.

Original languageEnglish
Pages (from-to)4858-4866
Number of pages9
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number21
DOIs
StatePublished - 1 Nov 2017

Fingerprint

Metabotropic Glutamate 5 Receptor
Dopamine Plasma Membrane Transport Proteins
Metabotropic Glutamate Receptors
Modulators
Pharmacokinetics
Niacinamide
Obsessive-Compulsive Disorder
Rats
Hydrogen
Assays
Hydrogen bonds
Screening
Pharmacology
pyridine

Keywords

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

Cite this

Felts, Andrew S. ; Rodriguez, Alice L. ; Morrison, Ryan D. ; Bollinger, Katrina A. ; Venable, Daryl F. ; Blobaum, Anna L. ; Byers, Frank W. ; Thompson Gray, Analisa ; Daniels, J. Scott ; Niswender, Colleen M. ; Jones, Carrie K. ; Conn, P. Jeffrey ; Lindsley, Craig W. ; Emmitte, Kyle Allen. / 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. In: Bioorganic and Medicinal Chemistry Letters. 2017 ; Vol. 27, No. 21. pp. 4858-4866.
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title = "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",
abstract = "Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu5 NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu5 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 mGlu5 versus DAT.",
keywords = "Central nervous system (CNS), G-protein coupled receptor (GPCR), Heterocycle, Metabotropic glutamate receptor subtype 5 (mGlu), Negative allosteric modulator (NAM)",
author = "Felts, {Andrew S.} and Rodriguez, {Alice L.} and Morrison, {Ryan D.} and Bollinger, {Katrina A.} and Venable, {Daryl F.} and Blobaum, {Anna L.} and Byers, {Frank W.} and {Thompson Gray}, Analisa and Daniels, {J. Scott} and Niswender, {Colleen M.} and Jones, {Carrie K.} and Conn, {P. Jeffrey} and Lindsley, {Craig W.} and Emmitte, {Kyle Allen}",
year = "2017",
month = "11",
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doi = "10.1016/j.bmcl.2017.09.042",
language = "English",
volume = "27",
pages = "4858--4866",
journal = "Bioorganic and Medicinal Chemistry Letters",
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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 2017, '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', Bioorganic and Medicinal Chemistry Letters, vol. 27, no. 21, pp. 4858-4866. https://doi.org/10.1016/j.bmcl.2017.09.042

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

In: Bioorganic and Medicinal Chemistry Letters, Vol. 27, No. 21, 01.11.2017, p. 4858-4866.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - 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

AU - Felts, Andrew S.

AU - Rodriguez, Alice L.

AU - Morrison, Ryan D.

AU - Bollinger, Katrina A.

AU - Venable, Daryl F.

AU - Blobaum, Anna L.

AU - Byers, Frank W.

AU - Thompson Gray, Analisa

AU - Daniels, J. Scott

AU - Niswender, Colleen M.

AU - Jones, Carrie K.

AU - Conn, P. Jeffrey

AU - Lindsley, Craig W.

AU - Emmitte, Kyle Allen

PY - 2017/11/1

Y1 - 2017/11/1

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KW - Central nervous system (CNS)

KW - G-protein coupled receptor (GPCR)

KW - Heterocycle

KW - Metabotropic glutamate receptor subtype 5 (mGlu)

KW - Negative allosteric modulator (NAM)

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U2 - 10.1016/j.bmcl.2017.09.042

DO - 10.1016/j.bmcl.2017.09.042

M3 - Article

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SP - 4858

EP - 4866

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 21

ER -