jm5b00742_si_002.csv (2.5 kB)
Novel Octahydropyrrolo[3,4‑c]pyrroles Are Selective Orexin‑2 Antagonists: SAR Leading to a Clinical Candidate
dataset
posted on 2015-07-23, 00:00 authored by 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 YunThe
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.
