Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140).
Aminoquinolines
/ chemical synthesis
Animals
Caco-2 Cells
Dogs
Drug Design
Escherichia coli
/ drug effects
Humans
Madin Darby Canine Kidney Cells
Male
Mice, Inbred C57BL
Microsomes, Liver
/ metabolism
Migraine Disorders
/ drug therapy
Molecular Structure
Narcotic Antagonists
/ chemical synthesis
Oxadiazoles
/ chemical synthesis
Piperidines
/ chemical synthesis
Quinolines
/ chemical synthesis
Rats, Sprague-Dawley
Receptors, Opioid, kappa
/ antagonists & inhibitors
Salmonella typhimurium
/ drug effects
Small Molecule Libraries
/ chemical synthesis
Structure-Activity Relationship
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
28 02 2019
28 02 2019
Historique:
pubmed:
2
2
2019
medline:
4
3
2020
entrez:
2
2
2019
Statut:
ppublish
Résumé
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-2 H-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.
Identifiants
pubmed: 30707578
doi: 10.1021/acs.jmedchem.8b01679
pmc: PMC6395531
mid: NIHMS1010426
doi:
Substances chimiques
Aminoquinolines
0
BTRX-335140
0
Narcotic Antagonists
0
Oxadiazoles
0
Piperidines
0
Quinolines
0
Receptors, Opioid, kappa
0
Small Molecule Libraries
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1761-1780Subventions
Organisme : NINDS NIH HHS
ID : UH2 NS093030
Pays : United States
Références
Brain Res. 2001 Mar 2;893(1-2):121-34
pubmed: 11223000
Bioorg Med Chem Lett. 2014 May 1;24(9):2021-32
pubmed: 24690494
J Org Chem. 2007 Aug 17;72(17):6390-6
pubmed: 17658848
Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):7006-10
pubmed: 7624359
Brain Res. 1982 Sep 23;248(1):87-96
pubmed: 6289997
Chem Rev. 2005 May;105(5):1767-800
pubmed: 15884789
J Clin Pharmacol. 2014 Sep;54(9):968-78
pubmed: 24619932
Epilepsy Res. 1997 Oct;28(3):189-205
pubmed: 9332884
Neuropsychopharmacology. 2018 Aug;43(9):1805-1812
pubmed: 29463912
JAMA Psychiatry. 2014 Nov;71(11):1262-1271
pubmed: 25229257
Neuropsychopharmacology. 2005 Dec;30(12):2254-62
pubmed: 15988468
Am J Psychiatry. 2016 May 1;173(5):499-508
pubmed: 26869247
Expert Opin Drug Metab Toxicol. 2018 Apr;14(4):475-482
pubmed: 29621905
Neuropsychopharmacology. 2018 Mar;43(4):739-750
pubmed: 28857070
Brain Res. 2010 Feb 16;1314:44-55
pubmed: 19716811
J Neurol Sci. 1997 May 29;148(2):171-80
pubmed: 9129113
Brain Res. 1987 Jun 23;414(1):8-14
pubmed: 3040166
Annu Rev Biochem. 2004;73:953-90
pubmed: 15189164
Nat Rev Endocrinol. 2015 May;11(5):265-75
pubmed: 25781857
Brain. 2007 Apr;130(Pt 4):1017-28
pubmed: 17347252
Biol Psychiatry. 2012 Nov 15;72(10):871-9
pubmed: 22817868
Int J Neuropsychopharmacol. 2014 Oct 31;18(2):
pubmed: 25637376
Eur J Pharmacol. 2001 Jul 6;423(2-3):243-9
pubmed: 11448491
Psychopharmacology (Berl). 2013 Oct;229(3):435-52
pubmed: 23836029
J Pharmacol Exp Ther. 2006 Jan;316(1):440-7
pubmed: 16223871
Brain Res. 1993 Dec 31;632(1-2):209-15
pubmed: 8149229
Ann N Y Acad Sci. 1999 Jun 29;877:507-22
pubmed: 10415668
J Med Chem. 2011 Dec 8;54(23):8000-12
pubmed: 21958337
Front Endocrinol (Lausanne). 2016 Mar 30;7:25
pubmed: 27065946
AAPS J. 2011 Dec;13(4):565-75
pubmed: 21847689
Brain Res. 1987 Aug 25;418(2):343-8
pubmed: 2823963
Endocr Rev. 2001 Dec;22(6):724-63
pubmed: 11739329
Science. 1982 Jan 22;215(4531):413-5
pubmed: 6120570
Mol Pharmacol. 2003 Jun;63(6):1256-72
pubmed: 12761335
ACS Chem Neurosci. 2012 Jan 18;3(1):50-68
pubmed: 22267984
BMC Pharmacol. 2012 May 29;12:5
pubmed: 22642416
Cephalalgia. 2017 Jul;37(8):780-794
pubmed: 28376659
Chem Rev. 2009 Jun;109(6):2652-71
pubmed: 19361199
Neuropharmacology. 2015 Oct;97:270-4
pubmed: 26044637
Neuropsychopharmacology. 2009 Jan;34(1):247
pubmed: 19079072
J Pharmacol Exp Ther. 2003 Apr;305(1):323-30
pubmed: 12649385
J Pharmacol Exp Ther. 2011 Nov;339(2):555-66
pubmed: 21821697
J Med Chem. 2011 Aug 25;54(16):5868-77
pubmed: 21744827