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

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
Bioorg Med Chem Lett. 2018 28 (15): 2641-2646

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

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 mGlu PAMs, leading to 9i (hmGlu EC = 43 nM; AhR activation = 2.3-fold).

Copyright © 2018 Elsevier Ltd. All rights reserved.

MeSH Terms (13)

Allosteric Regulation Animals Antiparkinson Agents Cytochrome P-450 CYP1A2 Cytochrome P-450 CYP1A2 Inducers Drug Discovery Enzyme Induction Humans Pyrazoles Pyridines Rats Receptors, Metabotropic Glutamate Structure-Activity Relationship

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