Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy

Rocco D Gogliotti; Darren W Engers; Pedro M Garcia-Barrantes; Joseph D Panarese; Patrick R Gentry; Anna L Blobaum; Ryan D Morrison; J Scott Daniels; Analisa D Thompson; Carrie K Jones; P Jeffrey Conn; Colleen M Niswender; Craig W Lindsley; Corey R Hopkins

doi:10.1016/j.bmcl.2016.04.041

Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy

Rocco D Gogliotti, Darren W Engers, Pedro M Garcia-Barrantes, Joseph D Panarese, Patrick R Gentry, Anna L Blobaum, Ryan D Morrison, J Scott Daniels, Analisa D Thompson, Carrie K Jones, P Jeffrey Conn, Colleen M Niswender, Craig W Lindsley, Corey R Hopkins

2 Citations (Scopus)

Abstract

This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50=95nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp=1.3), rat CLp=4.0mL/min/kg, t1/2=3.7h) and robust efficacy in our standard preclinical Parkinson's disease model, haloperidol-induced catalepsy (HIC).

Original language	English
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	26
Issue number	12
Pages (from-to)	2915-2919
Number of pages	5
ISSN	0960-894X
DOIs	https://doi.org/10.1016/j.bmcl.2016.04.041
Publication status	Published - 15 Jun 2016
Externally published	Yes

Keywords

Allosteric Regulation/drug effects
Amides/chemistry
Animals
Central Nervous System/drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Discovery
Humans
Molecular Structure
Picolines/chemistry
Rats
Receptors, Metabotropic Glutamate/antagonists & inhibitors
Structure-Activity Relationship

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Gogliotti, R. D., Engers, D. W., Garcia-Barrantes, P. M., Panarese, J. D., Gentry, P. R., Blobaum, A. L., Morrison, R. D., Daniels, J. S., Thompson, A. D., Jones, C. K., Conn, P. J., Niswender, C. M., Lindsley, C. W., & Hopkins, C. R. (2016). Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy. Bioorganic & Medicinal Chemistry Letters, 26(12), 2915-2919. https://doi.org/10.1016/j.bmcl.2016.04.041

Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy. / Gogliotti, Rocco D; Engers, Darren W; Garcia-Barrantes, Pedro M et al.

In: Bioorganic & Medicinal Chemistry Letters, Vol. 26, No. 12, 15.06.2016, p. 2915-2919.

Research output: Contribution to journal › Journal article › Research › peer-review

Gogliotti, RD, Engers, DW, Garcia-Barrantes, PM, Panarese, JD, Gentry, PR, Blobaum, AL, Morrison, RD, Daniels, JS, Thompson, AD, Jones, CK, Conn, PJ, Niswender, CM, Lindsley, CW & Hopkins, CR 2016, 'Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy', Bioorganic & Medicinal Chemistry Letters, vol. 26, no. 12, pp. 2915-2919. https://doi.org/10.1016/j.bmcl.2016.04.041

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abstract = "This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50=95nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp=1.3), rat CLp=4.0mL/min/kg, t1/2=3.7h) and robust efficacy in our standard preclinical Parkinson's disease model, haloperidol-induced catalepsy (HIC).",

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AU - Garcia-Barrantes, Pedro M

AU - Panarese, Joseph D

AU - Gentry, Patrick R

AU - Blobaum, Anna L

AU - Morrison, Ryan D

AU - Daniels, J Scott

AU - Thompson, Analisa D

AU - Jones, Carrie K

AU - Conn, P Jeffrey

AU - Niswender, Colleen M

AU - Lindsley, Craig W

AU - Hopkins, Corey R

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AB - This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50=95nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp=1.3), rat CLp=4.0mL/min/kg, t1/2=3.7h) and robust efficacy in our standard preclinical Parkinson's disease model, haloperidol-induced catalepsy (HIC).

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KW - Amides/chemistry

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KW - Central Nervous System/drug effects

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KW - Dose-Response Relationship, Drug

KW - Drug Discovery

KW - Humans

KW - Molecular Structure

KW - Picolines/chemistry

KW - Rats

KW - Receptors, Metabotropic Glutamate/antagonists & inhibitors

KW - Structure-Activity Relationship

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DO - 10.1016/j.bmcl.2016.04.041

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SN - 0960-894X

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JO - Bioorganic & Medicinal Chemistry Letters

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ER -

Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy

Abstract

Keywords

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