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

Research output: Contribution to journalArticle

1 Citation (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 = 95 nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp = 1.3), rat CLp = 4.0 mL/min/kg, t1/2 = 3.7 h) and robust efficacy in our standard preclinical Parkinson's disease model, haloperidol-induced catalepsy (HIC).

Original languageEnglish (US)
Pages (from-to)2915-2919
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number12
DOIs
StatePublished - Jun 15 2016

Fingerprint

Pulse amplitude modulation
Metabotropic Glutamate Receptors
Modulators
Catalepsy
Haloperidol
Parkinson Disease
Rats
Brain
Plasmas
picolinamide
metabotropic glutamate receptor 4

Keywords

  • Metabotropic glutamate receptor
  • Parkinson's disease
  • Positive allosteric modulator (PAM)
  • Structure-activity relationship (SAR)
  • mGlu

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

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 and Medicinal Chemistry Letters, Vol. 26, No. 12, 15.06.2016, p. 2915-2919.

Research output: Contribution to journalArticle

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 and Medicinal Chemistry Letters, vol. 26, no. 12, pp. 2915-2919. https://doi.org/10.1016/j.bmcl.2016.04.041
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 and Medicinal Chemistry Letters. 2016 ; Vol. 26, No. 12. pp. 2915-2919.
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