HCV NS5A replication complex inhibitors. Part 2: Investigation of stilbene prolinamides

doi:10.1016/j.bmcl.2012.08.049

Bioorganic & Medicinal Chemistry Letters

Volume 22, Issue 19, 1 October 2012, Pages 6063-6066

https://doi.org/10.1016/j.bmcl.2012.08.049 Get rights and content

Abstract

In a previous disclosure,¹ we reported the dimerization of an iminothiazolidinone to form 1, a contributor to the observed inhibition of HCV genotype 1b replicon activity. The dimer was isolated via bioassay-guided fractionation experiments and shown to be a potent inhibitor of genotype 1b HCV replication for which resistance mapped to the NS5A protein. The elements responsible for governing HCV inhibitory activity were successfully captured in the structurally simplified stilbene prolinamide 2. We describe herein the early SAR and profiling associated with stilbene prolinamides that culminated in the identification of analogs with PK properties sufficient to warrant continued commitment to this chemotype. These studies represent the key initial steps toward the discovery of daclatasvir (BMS-790052), a compound that has demonstrated clinical proof-of-concept for inhibiting the NS5A replication complex in the treatment of HCV infection.

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Acknowledgment

We thank Discovery Analytical Services (DAS) staff for providing HRMS and ¹H NMR spectral data.

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HCV NS5A replication complex inhibitors. Part 2: Investigation of stilbene prolinamides☆

Abstract

Graphical abstract

Section snippets

Acknowledgment

Clin. Microbiol. Infect.

Nat. Rev. Drug Discov.

N. Engl. J. Med.

Hepatology

Hepatology

Hepatology

Chem. Res. Toxicol.

J. Pharmcol. Toxicol. Methods

Annu. Rep. Med. Chem.

Nat. Rev. Drug Discov.

J. Med. Chem.

ACS Med. Chem. Lett.