Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- B]pyridines As Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2019 May 29

PMID 31136173

Citations 16

Authors

Sven Verdonck

Szu-Yuan Pu

Fiona J Sorrell

Jon M Elkins

Mathy Froeyen

Ling-Jie Gao

Laura I Prugar

Danielle E Dorosky

Jennifer M Brannan

Rina Barouch-Bentov

Stefan Knapp

John M Dye

Piet Herdewijn

Shirit Einav

Steven De Jonghe

Affiliations

Soon will be listed here.

Abstract

There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor-associated kinase 1 (AAK1) is a cellular serine-threonine protein kinase that functions as a key regulator of the clathrin-associated host adaptor proteins and regulates the intracellular trafficking of multiple unrelated RNA viruses. Moreover, AAK1 is overexpressed specifically in dengue virus-infected but not bystander cells. Because AAK1 is a promising antiviral drug target, we have embarked on an optimization campaign of a previously identified 7-azaindole analogue, yielding novel pyrrolo[2,3- b]pyridines with high AAK1 affinity. The optimized compounds demonstrate improved activity against dengue virus both in vitro and in human primary dendritic cells and the unrelated Ebola virus. These findings demonstrate that targeting cellular AAK1 may represent a promising broad-spectrum antiviral strategy.

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