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 A. Emmitte; Craig W. Lindsley

doi:10.1016/j.bmcl.2018.11.017

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 A. Emmitte, Craig W. Lindsley

Research output: Contribution to journal › Article

Abstract

This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu₅ 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 sp³ character, uniform CYP₄₅₀-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 language	English
Pages (from-to)	47-50
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2018.11.017
State	Published - 1 Jan 2019

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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., Blobaum, A. L., Niswender, C. M., Jones, C. K., Jeffrey Conn, P., Emmitte, K. A., & 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 A. ; 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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title = "Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5",

abstract = "This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 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 sp3 character, uniform CYP450-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.",

keywords = "CNS, Metabotropic glutamate receptor, Negative allosteric modulator (NAM), Structure-Activity Relationship (SAR), mGlu",

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

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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 A.; Lindsley, Craig W.

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

Research output: Contribution to journal › Article

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AU - Felts, Andrew S.

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AU - Brassard, Christopher J.

AU - Rodriguez, Alice L.

AU - Morrison, Ryan D.

AU - Scott Daniels, J.

AU - Blobaum, Anna L.

AU - Niswender, Colleen M.

AU - Jones, Carrie K.

AU - Jeffrey Conn, P.

AU - Emmitte, Kyle A.

AU - Lindsley, Craig W.

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AB - This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 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 sp3 character, uniform CYP450-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.

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10.1016/j.bmcl.2018.11.017

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