Multi-step parallel synthesis enabled optimization of benzofuran derivatives as pan-genotypic non-nucleoside inhibitors of HCV NS5B

被引：5

作者：

Xiao, Dong ^{[1
]}

Dai, Xing ^{[1
]}

Liu, Hong ^{[1
]}

He, Shuwen ^{[1
]}

Shi, Zhi-Cai ^{[1
]}

Ludmerer, Steven W. ^{[2
]}

Li, Fangbiao ^{[3
]}

Nargund, Ravi ^{[1
]}

Palani, Anandan ^{[1
]}

机构：

[1] Merck & Co Inc, Dept Med Chem, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[2] Merck & Co Inc, Dept Biol, 770 Sumneytown Pike, West Point, PA 19486 USA

[3] Merck & Co Inc, Dept Drug Metab, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2020年 / 30卷 / 07期

关键词：

NS5B NNI inhibitors; Lead optimization; Multi-step parallel libraries; Pan-genotypic potency; HEPATITIS-C VIRUS; MEDICINAL CHEMISTS; DISCOVERY; EPIDEMIOLOGY; POLYMERASE; INFECTION;

D O I：

10.1016/j.bmcl.2020.127004

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In a lead optimization effort towards NS5B NNI inhibitors, two multi-step parallel libraries were designed and successfully synthesized. Through this effort we discovered compound 9B, which achieved rigorous and delicate balance of inhibition across the common genotypes and mutants with < 10 nM potency. In addition, the bicyclic compounds 9B exhibited improved FASSIF solubility over the tetracyclic compound MK-8876. This strategic approach demonstrated that, even within limited reaction scope, multi-step parallel libraries could provide access to more complex chemical space. This expedient access facilitates diverse, purpose-driven optimization of SAR and physicochemical properties.

引用

页数：6

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