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

被引：7

作者：

Fu, Jiping ^{[1
]}

Becker, Christopher ^{[1
]}

Cao, Li ^{[4
]}

Capparelli, Michael ^{[1
]}

Denay, Regis ^{[2
]}

Fujimoto, Roger ^{[1
]}

Gai, Yu ^{[4
]}

Gao, Zhaobo ^{[4
]}

Guenat, Christian ^{[2
]}

Karur, Subramanian ^{[1
]}

Kim, Hongyong ^{[4
]}

Li, Weikuan ^{[4
]}

Li, Xiaolin ^{[1
]}

Li, Wei ^{[4
]}

Lochmann, Thomas ^{[2
]}

Lu, Amy ^{[4
]}

Lu, Peichao ^{[1
]}

Luneau, Alexandre ^{[2
]}

Meier, Nicole ^{[3
]}

Mergo, Wosenu ^{[1
]}

Ng, Simon ^{[2
]}

Parker, David ^{[1
]}

Peng, Yunshan ^{[1
]}

Riss, Bernard ^{[3
]}

Rivkin, Alexey ^{[1
]}

Roggo, Silvio ^{[2
]}

Schroeder, Harald ^{[2
]}

Schuerch, Friedrich ^{[3
]}

Simmons, Robert L. ^{[1
]}

Sun, Feng ^{[4
]}

Sweeney, Zachary K. ^{[1
]}

Tjandra, Meiliana ^{[1
]}

Wang, Michael ^{[4
]}

Wang, Ruidong ^{[4
]}

Weiss, Andrew H. ^{[1
]}

Wenger, Nicolas ^{[3
]}

Wu, Quanbing ^{[4
]}

Xiong, Xin ^{[4
]}

Xu, Su ^{[4
]}

Xu, Wenjian ^{[1
]}

Yifru, Aregahegn ^{[1
]}

Zhao, Jibin ^{[4
]}

Zhou, Jianguang ^{[4
]}

Zurcher, Christian ^{[3
]}

Gallou, Fabrice ^{[3
]}

机构：

[1] Novartis Inst BioMed Res, 5300 Chiron Way, Emeryville, CA 94608 USA

[2] Novartis Inst BioMed Res, Novartis Campus, CH-4056 Basel, Switzerland

[3] Chem & Analyt Dev, CH-4002 Basel, Switzerland

[4] Suzhou Novartis Pharma Technol Co Ltd, Chem & Analyt Dev, Changshu 215537, Jiangsu, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2018年 / 26卷 / 04期

关键词：

Cyclosporin A derivative; Hepatitis C virus; Cyclophilin inhibitor; HCV PROTEASE INHIBITOR; NONIMMUNOSUPPRESSIVE CYCLOPHILIN INHIBITORS; MACROCYCLIZATION; BINDING; SCALE;

D O I：

10.1016/j.bmc.2017.09.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：957 / 969

页数：13

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