Novel Octahydropyrrolo[3,4-c]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical Candidate
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- 作者：Michael A. Letavic ; Pascal Bonaventure ; Nicholas I. Carruthers ; Christine Dugovic ; Tatiana Koudriakova ; Brian Lord ; Timothy W. Lovenberg ; Kiev S. Ly ; Neelakandha S. Mani ; Diane Nepomuceno ; Daniel J. Pippel ; Michele Rizzolio ; Jonathan E. Shelton ; Chandra R. Shah ; Brock T. Shireman ; Lana K. Young ; Sujin Yun
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：July 23, 2015
- 年：2015
- 卷：58
- 期：14
- 页码：5620-5636
- 全文大小：666K
- ISSN：1520-4804
文摘
The preclinical characterization of novel octahydropyrrolo[3,4-c]pyrroles that are potent and selective orexin-2 antagonists is described. Optimization of physicochemical and DMPK properties led to the discovery of compounds with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compound that progressed into human clinical trials for the treatment of primary insomnia. The synthesis, SAR, and optimization of the pharmacokinetic properties of this series of compounds as well as the identification of the clinical candidate, JNJ-42847922 (34), are described herein.