1. Academic Validation
  2. Inhibition of the hERG potassium ion channel by different non-nucleoside human cytomegalovirus polymerase antiviral inhibitor series and the exploration of variations on a pyrroloquinoline core to reduce cardiotoxicity potential

Inhibition of the hERG potassium ion channel by different non-nucleoside human cytomegalovirus polymerase antiviral inhibitor series and the exploration of variations on a pyrroloquinoline core to reduce cardiotoxicity potential

  • Bioorg Med Chem. 2023 May 1:85:117276. doi: 10.1016/j.bmc.2023.117276.
Appan Srinivas Kandadai 1 Bing Bai 1 Mohammad Rahim 2 Fusen Lin 3 Zhengxian Gu 3 Xinyi Qi 3 Xuecheng Zhang 3 Haiheng Dong 3 Ying Chen 3 John Shen 4 James A Nieman 5
Affiliations

Affiliations

  • 1 Li Ka Shing Applied Virology Institute and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
  • 2 Rane Pharmaceuticals, Inc., Edmonton, Alberta T6E 5V2, Canada.
  • 3 WuXi AppTec (Shanghai) Co., Ltd., Shanghai 200131, China.
  • 4 ProFoldin, 10 Technology Drive, Suite 40, Hudson, MA 01749-2791, USA.
  • 5 Li Ka Shing Applied Virology Institute and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada. Electronic address: jnieman@ualberta.ca.
Abstract

Many non-nucleoside human cytomegalovirus (HCMV) inhibitors have been reported in patent and scientific literature, however, none have reached commercialization despite the urgent need for new HCMV treatments. Herein we report select compounds from different templates that all had low micromolar human ether-à-go-go (hERG) ion channel IC50 values. We also describe a series of pyrroloquinoline derivatives that were designed and synthesized to understand the effect of various substitution on human cytomegalovirus (HCMV) polymerase activity, Antiviral activity, and hERG inhibition. These results demonstrated that hERG inhibition can be significantly altered based on the substitution on this template. An HCMV inhibitor with low hERG inhibition and reduced cytotoxicity is also described. The results suggest substitution can be fine tuned for the non-nucleoside polymerase inhibitors to reduce hERG inhibition and maintain HCMV Antiviral potency.

Keywords

DNA polymerase inhibitors; HCMV; Human cytomegalovirus; Non-nucleoside; Pyrroloquinoline; hERG inhibition.

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