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

doi:10.1016/j.bmcl.2018.06.034

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

Bioorg Med Chem Lett. 2018 Aug 15;28(15):2641-2646. doi: 10.1016/j.bmcl.2018.06.034. Epub 2018 Jun 19.

Authors

Darren W Engers¹, Sean R Bollinger¹, Julie L Engers¹, Joseph D Panarese¹, Megan M Breiner¹, Alison Gregro¹, Anna L Blobaum¹, Joanne J Bronson², Yong-Jin Wu², John E Macor², Alice L Rodriguez¹, Rocio Zamorano¹, P Jeffrey Conn¹, Craig W Lindsley³, Colleen M Niswender⁴, Corey R Hopkins⁵

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
² Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
³ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
⁴ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁵ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: corey.hopkins@unmc.edu.

PMID: 29958762
DOI: 10.1016/j.bmcl.2018.06.034

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).

Keywords: CYP induction; Parkinson’s disease; Positive allosteric modulator; Structure-activity relationship; mGlu4 PAM.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation / drug effects
Animals
Antiparkinson Agents / pharmacology
Cytochrome P-450 CYP1A2 / biosynthesis*
Cytochrome P-450 CYP1A2 Inducers / pharmacology*
Drug Discovery*
Enzyme Induction / drug effects
Humans
Pyrazoles / chemistry*
Pyrazoles / pharmacology*
Pyridines / chemistry*
Pyridines / pharmacology*
Rats
Receptors, Metabotropic Glutamate / drug effects*
Receptors, Metabotropic Glutamate / metabolism
Structure-Activity Relationship

Substances

Antiparkinson Agents
Cytochrome P-450 CYP1A2 Inducers
Pyrazoles
Pyridines
Receptors, Metabotropic Glutamate
Cytochrome P-450 CYP1A2
metabotropic glutamate receptor 4