@article{9017cd1b246844e8969693b08f82a52e,
title = "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",
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",
author = "Engers, {Darren W.} and Bollinger, {Sean R.} and Engers, {Julie L.} and Panarese, {Joseph D.} and Breiner, {Megan M.} and Alison Gregro and Blobaum, {Anna L.} and Bronson, {Joanne J.} and Wu, {Yong Jin} and Macor, {John E.} and Rodriguez, {Alice L.} and Rocio Zamorano and Conn, {P. Jeffrey} and Lindsley, {Craig W.} and Niswender, {Colleen M.} and Hopkins, {Corey R.}",
note = "Funding Information: The authors would like to acknowledge the technical assistance of Daryl Venable and Shan Liang in performing in vitro pharmacology studies. The authors would also like to thank the Michael J. Fox Foundation for Parkinson's Research and Bristol-Myers Squibb for their support of the program to develop mGlu Funding Information: The authors would like to acknowledge the technical assistance of Daryl Venable and Shan Liang in performing in vitro pharmacology studies. The authors would also like to thank the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research and Bristol-Myers Squibb for their support of the program to develop mGlu 4 PAMs. We also thank William K. Warren, Jr. and the William K. Warren Foundation who funded the William K. Warren, Jr. Chair in Medicine (to C.W.L.). Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",
year = "2018",
month = aug,
day = "15",
doi = "10.1016/j.bmcl.2018.06.034",
language = "English (US)",
volume = "28",
pages = "2641--2646",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "15",
}