Substituted Azabicyclo[2.2.1]heptanes as Selective Orexin-1 Antagonists: Discovery of JNJ-54717793

  • ACS Med Chem Lett. 2020 Apr 27;11(10):2002-2009. doi: 10.1021/acsmedchemlett.0c00085.
Cathy Préville  1 ,  Pascal Bonaventure  1 ,  Tatiana Koudriakova  1 ,  Brian Lord  1 ,  Diane Nepomuceno  1 ,  Michele Rizzolio  1 ,  Neelakandha Mani  1 ,  Kevin J Coe  1 ,  Anthony Ndifor  1 ,  Christine Dugovic  1 ,  Curt A Dvorak  1 ,  Heather Coate  1 ,  Daniel J Pippel  1 ,  Anne Fitzgerald  1 ,  Brett Allison  1 ,  Timothy W Lovenberg  1 ,  Nicholas I Carruthers  1 ,  Brock T Shireman  1
Affiliations
  • 1. Janssen Research & Development L.L.C., 3210 Merryfield Row, San Diego, California 92121, United States.
PMID: 33062185 DOI: 10.1021/acsmedchemlett.0c00085
Abstract

The orexin system consists of two neuropeptides (orexin-A and orexin-B) that exert their mode of action on two receptors (orexin-1 and orexin-2). While the role of the orexin-2 receptor is established as an important modulator of sleep wake states, the role of the orexin-1 receptor is believed to play a role in addiction, panic, or anxiety. In this manuscript, we describe the optimization of a nonselective substituted azabicyclo[2.2.1]heptane dual orexin receptor antagonist (DORA) into orally bioavailable, brain penetrating, selective orexin-1 receptor (OX1R) antagonists. This resulted in the discovery of our first candidate for clinical development, JNJ-54717793.

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