Discovery of Novel Pyrido[2,3-b]pyrazine Human Cytomegalovirus Polymerase Inhibitors with Broad Spectrum Antiherpetic Activity and Reduced hERG Inhibition.
Bing Bai, Appan Srinivas Kandadai, Mostofa Hena, Alexandr Belovodskiy, John Shen, Michael Houghton, James A Nieman
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引用次数: 0
Abstract
The development of non-nucleoside inhibitors targeting human cytomegalovirus (HCMV) polymerase presents a promising approach for enhancing therapeutic treatment for patients with sustained HCMV viremia. A series of non-nucleoside HCMV DNA polymerase inhibitors with various substitution groups at 2-postition of the novel pyrido[2,3-b]pyrazine core was synthesized and investigated. The study focused on optimizing HCMV polymerase inhibition while minimizing off-target inhibition of human ether-à-go-go (hERG) ion channel. Several compounds exhibited strong antiviral activity against HCMV (typical EC50 <1 µM), with favorable cytotoxicity profiles. A potent lead compound, 27, with an EC50 of 0.33 µM and improved aqueous solubility was identified. Further antiviral assessments revealed the potential of select compounds to target a broad spectrum of herpesviruses, including herpes simplex virus (HSV-1, HSV-2) and Epstein-Barr virus (EBV).
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