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 journalArticlepeer-review

26 Scopus citations


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
Issue number4
StatePublished - Feb 28 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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