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 | |
| State | Published - Feb 28 2019 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
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 journal › Article
}
TY - JOUR
T1 - Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140)
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
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85061926913&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061926913&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b01679
DO - 10.1021/acs.jmedchem.8b01679
M3 - Article
C2 - 30707578
AN - SCOPUS:85061926913
VL - 62
SP - 1761
EP - 1780
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 4
ER -