Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140)

Miguel Guerrero; Mariangela Urbano; Eun Kyong Kim; Ana M. Gamo; Sean Riley; Lusine Abgaryan; Nora Leaf; Lori Jean Van Orden; Steven J. Brown; Jennifer Y. Xie; Frank Porreca; Michael D. Cameron; Hugh Rosen; Edward Roberts

doi:10.1021/acs.jmedchem.8b01679

Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140)

Miguel Guerrero, Mariangela Urbano, Eun Kyong Kim, Ana M. Gamo, Sean Riley, Lusine Abgaryan, Nora Leaf, Lori Jean Van Orden, Steven J. Brown, Jennifer Y. Xie, Frank Porreca, Michael D. Cameron, Hugh Rosen, Edward Roberts

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

26 Scopus citations

Abstract

κ opioid receptor (KOR) antagonists are potential pharmacotherapies for the treatment of migraine and stress-related mood disorders including depression, anxiety, and drug abuse, thus the development of novel KOR antagonists with an improved potency/selectivity profile and medication-like duration of action has attracted the interest of the medicinal chemistry community. In this paper, we describe the discovery of 1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4 amine (CYM-53093, BTRX-335140) as a potent and selective KOR antagonist, endowed with favorable in vitro ADMET and in vivo pharmacokinetic profiles and medication-like duration of action in rat pharmacodynamic experiments. Orally administered CYM-53093 showed robust efficacy in antagonizing KOR agonist-induced prolactin secretion and in tail-flick analgesia in mice. CYM-53093 exhibited a broad selectivity over a panel of off-target proteins. This compound is in phase 1 clinical trials for the treatment of neuropsychiatric disorders wherein dynorphin is thought to contribute to the underlying pathophysiology.

Original language	English (US)
Pages (from-to)	1761-1780
Number of pages	20
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	4
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01679
State	Published - Feb 28 2019

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Guerrero, M., Urbano, M., Kim, E. K., Gamo, A. M., Riley, S., Abgaryan, L., Leaf, N., Van Orden, L. J., Brown, S. J., Xie, J. Y., Porreca, F., Cameron, M. D., Rosen, H., & Roberts, E. (2019). Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140). Journal of Medicinal Chemistry, 62(4), 1761-1780. https://doi.org/10.1021/acs.jmedchem.8b01679

Guerrero, M, Urbano, M, Kim, EK, Gamo, AM, Riley, S, Abgaryan, L, Leaf, N, Van Orden, LJ, Brown, SJ, Xie, JY, Porreca, F, Cameron, MD, Rosen, H & Roberts, E 2019, 'Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140)', Journal of Medicinal Chemistry, vol. 62, no. 4, pp. 1761-1780. https://doi.org/10.1021/acs.jmedchem.8b01679

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title = "Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140)",

abstract = "κ opioid receptor (KOR) antagonists are potential pharmacotherapies for the treatment of migraine and stress-related mood disorders including depression, anxiety, and drug abuse, thus the development of novel KOR antagonists with an improved potency/selectivity profile and medication-like duration of action has attracted the interest of the medicinal chemistry community. In this paper, we describe the discovery of 1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4 amine (CYM-53093, BTRX-335140) as a potent and selective KOR antagonist, endowed with favorable in vitro ADMET and in vivo pharmacokinetic profiles and medication-like duration of action in rat pharmacodynamic experiments. Orally administered CYM-53093 showed robust efficacy in antagonizing KOR agonist-induced prolactin secretion and in tail-flick analgesia in mice. CYM-53093 exhibited a broad selectivity over a panel of off-target proteins. This compound is in phase 1 clinical trials for the treatment of neuropsychiatric disorders wherein dynorphin is thought to contribute to the underlying pathophysiology.",

author = "Miguel Guerrero and Mariangela Urbano and Kim, {Eun Kyong} and Gamo, {Ana M.} and Sean Riley and Lusine Abgaryan and Nora Leaf and {Van Orden}, {Lori Jean} and Brown, {Steven J.} and Xie, {Jennifer Y.} and Frank Porreca and Cameron, {Michael D.} and Hugh Rosen and Edward Roberts",

note = "Funding Information: We thank Ronald B. Franklin and Paul C. Anderson for insightful scientific consultation during the course of the project and for their help in preparing the manuscript. This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) and BlackThorn Therapeutics. The grant is funded as part of the Blueprint Neurotherapeutics Network (BPN) of the NIH Blueprint for Neuroscience Research grant 1UH2 NS093030-01 (Edward Roberts, Hugh Rosen, Frank Porreca). Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",

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doi = "10.1021/acs.jmedchem.8b01679",

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AU - Guerrero, Miguel

AU - Urbano, Mariangela

AU - Kim, Eun Kyong

AU - Gamo, Ana M.

AU - Riley, Sean

AU - Abgaryan, Lusine

AU - Leaf, Nora

AU - Van Orden, Lori Jean

AU - Brown, Steven J.

AU - Xie, Jennifer Y.

AU - Porreca, Frank

AU - Cameron, Michael D.

AU - Rosen, Hugh

AU - Roberts, Edward

N1 - Funding Information: We thank Ronald B. Franklin and Paul C. Anderson for insightful scientific consultation during the course of the project and for their help in preparing the manuscript. This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) and BlackThorn Therapeutics. The grant is funded as part of the Blueprint Neurotherapeutics Network (BPN) of the NIH Blueprint for Neuroscience Research grant 1UH2 NS093030-01 (Edward Roberts, Hugh Rosen, Frank Porreca). Publisher Copyright: © 2019 American Chemical Society.

PY - 2019/2/28

Y1 - 2019/2/28

N2 - κ opioid receptor (KOR) antagonists are potential pharmacotherapies for the treatment of migraine and stress-related mood disorders including depression, anxiety, and drug abuse, thus the development of novel KOR antagonists with an improved potency/selectivity profile and medication-like duration of action has attracted the interest of the medicinal chemistry community. In this paper, we describe the discovery of 1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4 amine (CYM-53093, BTRX-335140) as a potent and selective KOR antagonist, endowed with favorable in vitro ADMET and in vivo pharmacokinetic profiles and medication-like duration of action in rat pharmacodynamic experiments. Orally administered CYM-53093 showed robust efficacy in antagonizing KOR agonist-induced prolactin secretion and in tail-flick analgesia in mice. CYM-53093 exhibited a broad selectivity over a panel of off-target proteins. This compound is in phase 1 clinical trials for the treatment of neuropsychiatric disorders wherein dynorphin is thought to contribute to the underlying pathophysiology.

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ER -

Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140)

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