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)

J Med Chem. 2019 Feb 28;62(4):1761-1780. doi: 10.1021/acs.jmedchem.8b01679. Epub 2019 Feb 13.

Affiliations

¹ Department of Molecular Medicine , The Scripps Research Institute , 10550 North Torrey Pines Road , La Jolla , California 92037 , United States.
² BlackThorn Therapeutics, Inc. 780 Brannan Street , San Francisco , California 94103 , United States.
³ Department of Pharmacology , University of Arizona , Tucson , Arizona 85724 , United States.
⁴ Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States.

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-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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Aminoquinolines / chemical synthesis
Aminoquinolines / pharmacokinetics
Aminoquinolines / therapeutic use*
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
Narcotic Antagonists / pharmacokinetics
Narcotic Antagonists / therapeutic use*
Oxadiazoles / chemical synthesis
Oxadiazoles / pharmacokinetics
Oxadiazoles / therapeutic use*
Piperidines / chemical synthesis
Piperidines / pharmacokinetics
Piperidines / therapeutic use*
Quinolines / chemical synthesis
Quinolines / pharmacokinetics
Quinolines / therapeutic use*
Rats, Sprague-Dawley
Receptors, Opioid, kappa / antagonists & inhibitors*
Salmonella typhimurium / drug effects
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / pharmacokinetics
Small Molecule Libraries / therapeutic use
Structure-Activity Relationship

Substances

Aminoquinolines
BTRX-335140
Narcotic Antagonists
Oxadiazoles
Piperidines
Quinolines
Receptors, Opioid, kappa
Small Molecule Libraries

Grants and funding

UH2 NS093030/NS/NINDS NIH HHS/United States