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 Citationer (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).

Originalsprog	Engelsk
Tidsskrift	Bioorganic & Medicinal Chemistry Letters
Vol/bind	26
Udgave nummer	12
Sider (fra-til)	2915-2919
Antal sider	5
ISSN	0960-894X
DOI	https://doi.org/10.1016/j.bmcl.2016.04.041
Status	Udgivet - 15 jun. 2016
Udgivet eksternt	Ja

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10.1016/j.bmcl.2016.04.041

Citationsformater

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.
I: Bioorganic & Medicinal Chemistry Letters, Bind 26, Nr. 12, 15.06.2016, s. 2915-2919.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 26, nr. 12, s. 2915-2919. https://doi.org/10.1016/j.bmcl.2016.04.041

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

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

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doi = "10.1016/j.bmcl.2016.04.041",

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journal = "Bioorganic & Medicinal Chemistry Letters",

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AU - Gogliotti, Rocco D

AU - Engers, Darren W

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

PY - 2016/6/15

Y1 - 2016/6/15

N2 - 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).

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).

KW - Allosteric Regulation/drug effects

KW - Amides/chemistry

KW - Animals

KW - Central Nervous System/drug effects

KW - Disease Models, Animal

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

U2 - 10.1016/j.bmcl.2016.04.041

DO - 10.1016/j.bmcl.2016.04.041

M3 - Journal article

C2 - 27131990

SN - 0960-894X

VL - 26

SP - 2915

EP - 2919

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 12

ER -

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

Abstract

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