Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation

Andrew S. Felts, Alice L. Rodriguez, Anna L. Blobaum, Ryan D. Morrison, Brittney S. Bates, Analisa Thompson Gray, Jerri M. Rook, Mohammed N. Tantawy, Frank W. Byers, Sichen Chang, Daryl F. Venable, Vincent B. Luscombe, Gilles D. Tamagnan, Colleen M. Niswender, J. Scott Daniels, Carrie K. Jones, P. Jeffrey Conn, Craig W. Lindsley, Kyle Allen Emmitte

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu5 PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.

Original languageEnglish
Pages (from-to)5072-5085
Number of pages14
JournalJournal of Medicinal Chemistry
Volume60
Issue number12
DOIs
StatePublished - 22 Jun 2017

Fingerprint

Metabotropic Glutamate 5 Receptor
Allosteric Site
Macaca fascicularis
Papio
Neurodegenerative Diseases
Psychiatry
Binding Sites
Clinical Trials
Ligands
picolinamide

Cite this

Felts, Andrew S. ; Rodriguez, Alice L. ; Blobaum, Anna L. ; Morrison, Ryan D. ; Bates, Brittney S. ; Thompson Gray, Analisa ; Rook, Jerri M. ; Tantawy, Mohammed N. ; Byers, Frank W. ; Chang, Sichen ; Venable, Daryl F. ; Luscombe, Vincent B. ; Tamagnan, Gilles D. ; Niswender, Colleen M. ; Daniels, J. Scott ; Jones, Carrie K. ; Conn, P. Jeffrey ; Lindsley, Craig W. ; Emmitte, Kyle Allen. / Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238) : A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 12. pp. 5072-5085.
@article{d12b662f565e4e688f02a55cef08af2c,
title = "Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation",
abstract = "Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu5 PET ligand demonstrated 50{\%} receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.",
author = "Felts, {Andrew S.} and Rodriguez, {Alice L.} and Blobaum, {Anna L.} and Morrison, {Ryan D.} and Bates, {Brittney S.} and {Thompson Gray}, Analisa and Rook, {Jerri M.} and Tantawy, {Mohammed N.} and Byers, {Frank W.} and Sichen Chang and Venable, {Daryl F.} and Luscombe, {Vincent B.} and Tamagnan, {Gilles D.} and Niswender, {Colleen M.} and Daniels, {J. Scott} and Jones, {Carrie K.} and Conn, {P. Jeffrey} and Lindsley, {Craig W.} and Emmitte, {Kyle Allen}",
year = "2017",
month = "6",
day = "22",
doi = "10.1021/acs.jmedchem.7b00410",
language = "English",
volume = "60",
pages = "5072--5085",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "12",

}

Felts, AS, Rodriguez, AL, Blobaum, AL, Morrison, RD, Bates, BS, Thompson Gray, A, Rook, JM, Tantawy, MN, Byers, FW, Chang, S, Venable, DF, Luscombe, VB, Tamagnan, GD, Niswender, CM, Daniels, JS, Jones, CK, Conn, PJ, Lindsley, CW & Emmitte, KA 2017, 'Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation', Journal of Medicinal Chemistry, vol. 60, no. 12, pp. 5072-5085. https://doi.org/10.1021/acs.jmedchem.7b00410

Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238) : A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation. / Felts, Andrew S.; Rodriguez, Alice L.; Blobaum, Anna L.; Morrison, Ryan D.; Bates, Brittney S.; Thompson Gray, Analisa; Rook, Jerri M.; Tantawy, Mohammed N.; Byers, Frank W.; Chang, Sichen; Venable, Daryl F.; Luscombe, Vincent B.; Tamagnan, Gilles D.; Niswender, Colleen M.; Daniels, J. Scott; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.; Emmitte, Kyle Allen.

In: Journal of Medicinal Chemistry, Vol. 60, No. 12, 22.06.2017, p. 5072-5085.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238)

T2 - A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation

AU - Felts, Andrew S.

AU - Rodriguez, Alice L.

AU - Blobaum, Anna L.

AU - Morrison, Ryan D.

AU - Bates, Brittney S.

AU - Thompson Gray, Analisa

AU - Rook, Jerri M.

AU - Tantawy, Mohammed N.

AU - Byers, Frank W.

AU - Chang, Sichen

AU - Venable, Daryl F.

AU - Luscombe, Vincent B.

AU - Tamagnan, Gilles D.

AU - Niswender, Colleen M.

AU - Daniels, J. Scott

AU - Jones, Carrie K.

AU - Conn, P. Jeffrey

AU - Lindsley, Craig W.

AU - Emmitte, Kyle Allen

PY - 2017/6/22

Y1 - 2017/6/22

N2 - Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu5 PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.

AB - Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu5 PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.

UR - http://www.scopus.com/inward/record.url?scp=85021142722&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.7b00410

DO - 10.1021/acs.jmedchem.7b00410

M3 - Article

C2 - 28530802

AN - SCOPUS:85021142722

VL - 60

SP - 5072

EP - 5085

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 12

ER -