Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140)

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.