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 › peer-review

2 Scopus citations

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

Keywords

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

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10.1016/j.bmcl.2018.11.017

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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.}",

note = "Funding Information: We thank the NIH and NIMH for funding ( U19MH097056 ). We also thank William K. Warren, Jr. and the William K. Warren Foundation who funded the William K. Warren, Jr. Chair in Medicine (to C.W.L.). Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

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doi = "10.1016/j.bmcl.2018.11.017",

language = "English",

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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 › peer-review

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T1 - Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

AU - Felts, Andrew S.

AU - Bollinger, Katrina A.

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.

N1 - Funding Information: We thank the NIH and NIMH for funding ( U19MH097056 ). We also thank William K. Warren, Jr. and the William K. Warren Foundation who funded the William K. Warren, Jr. Chair in Medicine (to C.W.L.). Publisher Copyright: © 2018 Elsevier Ltd

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

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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KW - Metabotropic glutamate receptor

KW - Negative allosteric modulator (NAM)

KW - Structure-Activity Relationship (SAR)

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DO - 10.1016/j.bmcl.2018.11.017

M3 - Article

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AN - SCOPUS:85056617861

VL - 29

SP - 47

EP - 50

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 1

ER -

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

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