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 Scopus citations

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)
Pages (from-to)2641-2646
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number15
DOIs
StatePublished - Aug 15 2018

Keywords

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

ASJC Scopus subject areas

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

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    Engers, D. W., Bollinger, S. R., Engers, J. L., Panarese, J. D., Breiner, M. M., Gregro, A., Blobaum, A. L., Bronson, J. J., Wu, Y. J., Macor, J. E., Rodriguez, A. L., Zamorano, R., Conn, P. J., Lindsley, C. W., Niswender, C. M., & Hopkins, C. R. (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, 28(15), 2641-2646. https://doi.org/10.1016/j.bmcl.2018.06.034