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Design, synthesis and identification of silicon-containing HCV NS5A inhibitors with pan-genotype activity.

Abstract：

:Modification of a HCV NS5A inhibitor, ombitasvir, led to the identification of 10d with improved pan-genotype NS5A inhibition and better pharmacokinetic properties. The key structural changes to ombitasvir include bioisosteric replacement of carbon with silicon atom. Compared with ombitasvir, the activity of anti-HCV genotypes (GT 1 to 6) of 10d is increased to some extent, especially the inhibitory activity against genotype 3a and 6a is increased by more than seven times, and the dog's in vivo pharmacokinetics properties were also superior to ombitasvir. Further drug evaluation showed that 10d was similar to ombitasvir on plasma protein binding and liver distribution profiles, with no cytotoxicity and no inhibitory effect on both CYP 450 and hERG ligand binding. However, permeability assay results indicated that 10d was not the substrate of P-gp or BCRP transporter, which is different from that of ombitasvir. The results of a 14-day repeat-dose toxicity study identified no toxicity with 10d. Our findings in preclinical tests suggest that the silicon-containing compound 10d could be worthy of continued study as a potential drug candidate.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Liu B,Gai K,Qin H,Liu X,Cao Y,Lu Q,Lu D,Chen D,Shen H,Song W,Zhang Y,Wang X,Xu H,Zhang Y

doi

10.1016/j.ejmech.2018.02.025

subject

Has Abstract

pub_date

2018-03-25 00:00:00

pages

95-105

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(18)30153-3

journal_volume

148

pub_type

杂志文章

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