Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

Andrew S. Felts, Katrina A. Bollinger, Christopher J. Brassard, Alice L. Rodriguez, Ryan D. Morrison, J. Scott Daniels, Anna L. Blobaum, Colleen M. Niswender, Carrie K. Jones, P. Jeffrey Conn, Kyle Allen Emmitte, Craig W. Lindsley

Research output: Contribution to journalArticleResearchpeer-review

Abstract

This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu 5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp 3 character, uniform CYP 450 -mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.

Original languageEnglish
Pages (from-to)47-50
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number1
DOIs
StatePublished - 1 Jan 2019

Fingerprint

Aldehyde Oxidase
Metabotropic Glutamate 5 Receptor
Metabotropic Glutamate Receptors
Metabolism
Modulators
Metabolites
Ether
Toxicology
Primates
Libraries
Ligands
pyrimidine
alkoxyl radical

Keywords

  • CNS
  • Metabotropic glutamate receptor
  • Negative allosteric modulator (NAM)
  • Structure-Activity Relationship (SAR)
  • mGlu

Cite this

Felts, A. S., Bollinger, K. A., Brassard, C. J., Rodriguez, A. L., Morrison, R. D., Scott Daniels, J., ... Lindsley, C. W. (2019). Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. Bioorganic and Medicinal Chemistry Letters, 29(1), 47-50. https://doi.org/10.1016/j.bmcl.2018.11.017
Felts, Andrew S. ; Bollinger, Katrina A. ; Brassard, Christopher J. ; Rodriguez, Alice L. ; Morrison, Ryan D. ; Scott Daniels, J. ; Blobaum, Anna L. ; Niswender, Colleen M. ; Jones, Carrie K. ; Jeffrey Conn, P. ; Emmitte, Kyle Allen ; Lindsley, Craig W. / Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. In: Bioorganic and Medicinal Chemistry Letters. 2019 ; Vol. 29, No. 1. pp. 47-50.
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Felts, AS, Bollinger, KA, Brassard, CJ, Rodriguez, AL, Morrison, RD, Scott Daniels, J, Blobaum, AL, Niswender, CM, Jones, CK, Jeffrey Conn, P, Emmitte, KA & Lindsley, CW 2019, 'Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5' Bioorganic and Medicinal Chemistry Letters, vol. 29, no. 1, pp. 47-50. https://doi.org/10.1016/j.bmcl.2018.11.017

Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. / Felts, Andrew S.; Bollinger, Katrina A.; Brassard, Christopher J.; Rodriguez, Alice L.; Morrison, Ryan D.; Scott Daniels, J.; Blobaum, Anna L.; Niswender, Colleen M.; Jones, Carrie K.; Jeffrey Conn, P.; Emmitte, Kyle Allen; Lindsley, Craig W.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 1, 01.01.2019, p. 47-50.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Rodriguez, Alice L.

AU - Morrison, Ryan D.

AU - Scott Daniels, J.

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AU - Niswender, Colleen M.

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AU - Emmitte, Kyle Allen

AU - Lindsley, Craig W.

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