Substituted Azabicyclo[2.2.1]heptanes as Selective Orexin-1 Antagonists: Discovery of JNJ-54717793,ACS Medicinal Chemistry Letters

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Substituted Azabicyclo[2.2.1]heptanes as Selective Orexin-1 Antagonists: Discovery of JNJ-54717793
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-04-27 , 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

Affiliation

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.

中文翻译：

取代的氮杂双环 [2.2.1] 庚烷作为选择性 Orexin-1 拮抗剂：JNJ-54717793 的发现

食欲素系统由两种神经肽（食欲素-A和食欲素-B）组成，它们对两种受体（食欲素-1和食欲素-2）发挥作用。虽然orexin-2 受体的作用被确立为睡眠觉醒状态的重要调节剂，但orexin-1 受体的作用被认为在成瘾、恐慌或焦虑中起作用。在这份手稿中，我们描述了将非选择性取代的氮杂双环 [2.2.1] 庚烷双食欲素受体拮抗剂 (DORA) 优化为口服生物可利用的、脑穿透性的、选择性的食欲素-1 受体 (OX1R) 拮抗剂。这导致我们发现了我们的第一个临床开发候选者，JNJ-54717793。

更新日期：2020-04-27

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