Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu4 positive allosteric modulators that mitigate CYP1A2 induction liability

Darren W. Engers, Sean R. Bollinger, Julie L. Engers, Joseph D. Panarese, Megan M. Breiner, Alison Gregro, Anna L. Blobaum, Joanne J. Bronson, Yong Jin Wu, John E. Macor, Alice L. Rodriguez, Rocio Zamorano, P. Jeffrey Conn, Craig W. Lindsley, Colleen M. Niswender, Corey R Hopkins

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu4 PAMs, leading to 9i (hmGlu4 EC50 = 43 nM; AhR activation = 2.3-fold).

Original languageEnglish (US)
JournalBioorganic and Medicinal Chemistry Letters
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP1A2
Scaffolds
Modulators
Amines
Chemical activation
Parkinson Disease
Rodentia
Pulse amplitude modulation
pyridine

Keywords

  • CYP induction
  • mGlu4 PAM
  • Parkinson's disease
  • Positive allosteric modulator
  • Structure-activity relationship

ASJC Scopus subject areas

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

Cite this

Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu4 positive allosteric modulators that mitigate CYP1A2 induction liability. / Engers, Darren W.; Bollinger, Sean R.; Engers, Julie L.; Panarese, Joseph D.; Breiner, Megan M.; Gregro, Alison; Blobaum, Anna L.; Bronson, Joanne J.; Wu, Yong Jin; Macor, John E.; Rodriguez, Alice L.; Zamorano, Rocio; Conn, P. Jeffrey; Lindsley, Craig W.; Niswender, Colleen M.; Hopkins, Corey R.

In: Bioorganic and Medicinal Chemistry Letters, 01.01.2018.

Research output: Contribution to journalArticle

Engers, DW, Bollinger, SR, Engers, JL, Panarese, JD, Breiner, MM, Gregro, A, Blobaum, AL, Bronson, JJ, Wu, YJ, Macor, JE, Rodriguez, AL, Zamorano, R, Conn, PJ, Lindsley, CW, Niswender, CM & Hopkins, CR 2018, 'Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu4 positive allosteric modulators that mitigate CYP1A2 induction liability', Bioorganic and Medicinal Chemistry Letters. https://doi.org/10.1016/j.bmcl.2018.06.034
Engers, Darren W. ; Bollinger, Sean R. ; Engers, Julie L. ; Panarese, Joseph D. ; Breiner, Megan M. ; Gregro, Alison ; Blobaum, Anna L. ; Bronson, Joanne J. ; Wu, Yong Jin ; Macor, John E. ; Rodriguez, Alice L. ; Zamorano, Rocio ; Conn, P. Jeffrey ; Lindsley, Craig W. ; Niswender, Colleen M. ; Hopkins, Corey R. / Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu4 positive allosteric modulators that mitigate CYP1A2 induction liability. In: Bioorganic and Medicinal Chemistry Letters. 2018.
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AU - Macor, John E.

AU - Rodriguez, Alice L.

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