2. Academic Validation
  3. Substituted Azabicyclo[2.2.1]heptanes as Selective Orexin-1 Antagonists: Discovery of JNJ-54717793

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

Affiliation

  • 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.

Figures
Products