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

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

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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).

Original language	English (US)
Pages (from-to)	2641-2646
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	28
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2018.06.034
State	Published - Aug 15 2018
Externally published	Yes

Keywords

CYP induction
Parkinson's disease
Positive allosteric modulator
Structure-activity relationship
mGlu4 PAM

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmcl.2018.06.034

Cite this

Engers, D. W., Bollinger, S. R., Engers, J. L., Panarese, J. D., Breiner, M. M., Gregro, A., Blobaum, A. L., Bronson, J. J., Wu, Y. J., Macor, J. E., Rodriguez, A. L., Zamorano, R., Conn, P. J., Lindsley, C. W., Niswender, C. M., & Hopkins, C. R. (2018). 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. Bioorganic and Medicinal Chemistry Letters, 28(15), 2641-2646. https://doi.org/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. / Engers, Darren W.; Bollinger, Sean R.; Engers, Julie L. et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 28, No. 15, 15.08.2018, p. 2641-2646.

Research output: Contribution to journal › Article › peer-review

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 2018, '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', Bioorganic and Medicinal Chemistry Letters, vol. 28, no. 15, pp. 2641-2646. https://doi.org/10.1016/j.bmcl.2018.06.034

Engers DW, Bollinger SR, Engers JL, Panarese JD, Breiner MM, Gregro A et al. 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. Bioorganic and Medicinal Chemistry Letters. 2018 Aug 15;28(15):2641-2646. doi: 10.1016/j.bmcl.2018.06.034

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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",

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doi = "10.1016/j.bmcl.2018.06.034",

language = "English (US)",

volume = "28",

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T1 - 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

AU - Engers, Darren W.

AU - Bollinger, Sean R.

AU - Engers, Julie L.

AU - Panarese, Joseph D.

AU - Breiner, Megan M.

AU - Gregro, Alison

AU - Blobaum, Anna L.

AU - Bronson, Joanne J.

AU - Wu, Yong Jin

AU - Macor, John E.

AU - Rodriguez, Alice L.

AU - Zamorano, Rocio

AU - Conn, P. Jeffrey

AU - Lindsley, Craig W.

AU - Niswender, Colleen M.

AU - Hopkins, Corey R.

N1 - 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’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: © 2018 Elsevier Ltd

PY - 2018/8/15

Y1 - 2018/8/15

N2 - 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).

AB - 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).

KW - CYP induction

KW - Parkinson's disease

KW - Positive allosteric modulator

KW - Structure-activity relationship

KW - mGlu4 PAM

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