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

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.

SUBMITTER: Preville C

PROVIDER: S-EPMC7549262 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Préville Cathy C Bonaventure Pascal P Koudriakova Tatiana T Lord Brian B Nepomuceno Diane D Rizzolio Michele M Mani Neelakandha N Coe Kevin J KJ Ndifor Anthony A Dugovic Christine C Dvorak Curt A CA Coate Heather H Pippel Daniel J DJ Fitzgerald Anne A Allison Brett B Lovenberg Timothy W TW Carruthers Nicholas I NI Shireman Brock T BT

ACS medicinal chemistry letters 20200427 10

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 bi ...[more]

PMID: 33062185

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