Gallou, Fabrice and Fu, Jiping (2017) Development of a Cyclosporin derivative and of its synthesis as cyclophilin inhibitor with excellent anti-HCV potency. Bioorganic and Medecinal Chemistry.

Abstract

Synthetic modification of cyclosporine A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-HCV potency, decreased transporter inhibition and pharmacokinetics suitable for coadministration with other drugs. Herein, we disclosed the evolution of the synthetic strategy to NIM258 from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in P4 fragment was constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as chiral ligand. Identification of advanced cyrstalline intermediates enabled practical supply of advanced compounds. Finally, the macrocyclization was carried out at 10% weight concentration by an unprecedented “slow release” concept.

Item Type:	Article
Date Deposited:	24 Oct 2017 00:45
Last Modified:	24 Oct 2017 00:45
URI:	https://oak.novartis.com/id/eprint/32876