Development of a cyclosporin A derivative with excellent anti-hepatitis C virus potency

Publication date: Available online 7 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Jiping Fu, Christopher Becker, Li Cao, Michael Capparelli, Regis Denay, Roger Fujimoto, Yu Gai, Zhaobo Gao, Christian Guenat, Subramanian Karur, Hongyong Kim, Weikuan Li, Xiaolin Li, Wei Li, Thomas Lochmann, Amy Lu, Peichao Lu, Alexandre Luneau, Nicole Meier, Wosenu Mergo, Simon Ng, David Parker, Yunshan Peng, Bernard Riss, Alexey Rivkin, Silvio Roggo, Harald Schroeder, Friedrich Schuerch, Robert L. Simmons, Feng Sun, Zachary K. Sweeney, Meiliana Tjandra, Michael Wang, Ruidong Wang, Andrew H. Weiss, Nicolas Wenger, Quanbing Wu, Xin Xiong, Su Xu, Wenjian Xu, Aregahegn Yifru, Jibin Zhao, Jianguang Zhou, Christian Zürcher, Fabrice Gallou
Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.

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