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
| Autor: | John E. Macor, Darren W. Engers, Julie L. Engers, Colleen M. Niswender, P. Jeffrey Conn, Rocio Zamorano, Alice L. Rodriguez, Joanne J. Bronson, Sean R. Bollinger, Anna L. Blobaum, Joseph D. Panarese, Craig W. Lindsley, Alison R. Gregro, Corey R. Hopkins, Wu Yong Jin, Megan M. Breiner |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Scaffold Chemistry Stereochemistry Organic Chemistry Clinical Biochemistry Allosteric regulation CYP1A2 Pharmaceutical Science Biochemistry 03 medical and health sciences 030104 developmental biology 0302 clinical medicine In vivo Drug Discovery Molecular Medicine Potency Amine gas treating Selectivity Molecular Biology 030217 neurology & neurosurgery |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 28:2641-2646 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2018.06.034 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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