Standard
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; Panarese, Joseph D; Gentry, Patrick R; Blobaum, Anna L; Morrison, Ryan D; Daniels, J Scott; Thompson, Analisa D; Jones, Carrie K; Conn, P Jeffrey; Niswender, Colleen M; Lindsley, Craig W; Hopkins, Corey R.
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
Harvard
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.2016.04.041APA
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.2016.04.041Vancouver
Gogliotti RD, Engers DW, Garcia-Barrantes PM, Panarese JD, Gentry PR, Blobaum AL et al.
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. 2016 Jun 15;26(12):2915-2919.
https://doi.org/10.1016/j.bmcl.2016.04.041Author
Gogliotti, Rocco D ; Engers, Darren W ; Garcia-Barrantes, Pedro M ; Panarese, Joseph D ; Gentry, Patrick R ; Blobaum, Anna L ; Morrison, Ryan D ; Daniels, J Scott ; Thompson, Analisa D ; Jones, Carrie K ; Conn, P Jeffrey ; Niswender, Colleen M ; Lindsley, Craig W ; Hopkins, Corey R. / Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy. In: Bioorganic & Medicinal Chemistry Letters. 2016 ; Vol. 26, No. 12. pp. 2915-2919.
Bibtex
@article{7cdfc909e1dc4783b916a3ac63abf825,
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).",
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",
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}",
note = "Copyright {\textcopyright} 2016 Elsevier Ltd. All rights reserved.",
year = "2016",
month = jun,
day = "15",
doi = "10.1016/j.bmcl.2016.04.041",
language = "English",
volume = "26",
pages = "2915--2919",
journal = "Bioorganic & Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Pergamon Press",
number = "12",
}
RIS
TY - JOUR
T1 - Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy
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
N1 - Copyright © 2016 Elsevier Ltd. All rights reserved.
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
VL - 26
SP - 2915
EP - 2919
JO - Bioorganic & Medicinal Chemistry Letters
JF - Bioorganic & Medicinal Chemistry Letters
SN - 0960-894X
IS - 12
ER -
