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).
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Authors | 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 |
Journal | Bioorganic & medicinal chemistry letters
(Bioorg Med Chem Lett)
Vol. 28
Issue 15
Pg. 2641-2646
(08 15 2018)
ISSN: 1464-3405 [Electronic] England |
PMID | 29958762
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2018 Elsevier Ltd. All rights reserved. |
Chemical References |
- Antiparkinson Agents
- Cytochrome P-450 CYP1A2 Inducers
- Pyrazoles
- Pyridines
- Receptors, Metabotropic Glutamate
- Cytochrome P-450 CYP1A2
- metabotropic glutamate receptor 4
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Topics |
- 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, pharmacology)
- Pyridines
(chemistry, pharmacology)
- Rats
- Receptors, Metabotropic Glutamate
(drug effects, metabolism)
- Structure-Activity Relationship
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