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.
Miguel Guerrero  1 ,  Mariangela Urbano  1 ,  Eun-Kyong Kim  1 ,  Ana M Gamo  1 ,  Sean Riley  1 ,  Lusine Abgaryan  1 ,  Nora Leaf  1 ,  Lori Jean Van Orden  2 ,  Steven J Brown  1 ,  Jennifer Y Xie  3 ,  Frank Porreca  3 ,  Michael D Cameron  4 ,  Hugh Rosen  1 ,  Edward Roberts  1
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.
PMID: 30707578 DOI: 10.1021/acs.jmedchem.8b01679
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.

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