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 journalArticle

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 languageEnglish (US)
Pages (from-to)1761-1780
Number of pages20
JournalJournal of Medicinal Chemistry
Volume62
Issue number4
DOIs
StatePublished - Feb 28 2019

Fingerprint

kappa Opioid Receptor
Narcotic Antagonists
Pyrans
Dynorphins
Clinical Trials, Phase I
Pharmaceutical Chemistry
Opioid Receptors
Migraine Disorders
Mood Disorders
Prolactin
Analgesia
Substance-Related Disorders
Amines
Tail
Anxiety
Pharmacokinetics
Depression
Drug Therapy
Therapeutics
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Guerrero, M., Urbano, M., Kim, E. K., Gamo, A. M., Riley, S., Abgaryan, L., ... 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

Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140). / Guerrero, Miguel; Urbano, Mariangela; Kim, Eun Kyong; Gamo, Ana M.; Riley, Sean; Abgaryan, Lusine; Leaf, Nora; Van Orden, Lori Jean; Brown, Steven J.; Xie, Jennifer Y.; Porreca, Frank; Cameron, Michael D.; Rosen, Hugh; Roberts, Edward.

In: Journal of Medicinal Chemistry, Vol. 62, No. 4, 28.02.2019, p. 1761-1780.

Research output: Contribution to journalArticle

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
Guerrero, Miguel ; Urbano, Mariangela ; Kim, Eun Kyong ; Gamo, Ana M. ; Riley, Sean ; Abgaryan, Lusine ; Leaf, Nora ; Van Orden, Lori Jean ; Brown, Steven J. ; Xie, Jennifer Y. ; Porreca, Frank ; Cameron, Michael D. ; Rosen, Hugh ; Roberts, Edward. / Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140). In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 4. pp. 1761-1780.
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