A New Approach of Mitigating CYP3A4 Induction Led to the Discovery of Potent Hepatitis B Virus (HBV) Capsid Inhibitor with Optimal ADMET Profiles
| Autor: | Hong C. Shen, Zhu Wei, Zongxing Qiu, Hongxia Qiu, Sheng Zhong, Zheng Zhou, Weixing Zhang, Xue Zhou, Guozhi Tang, Fabian Dey, Guang Yang, Xianfeng Lin, Jianxun Xie, Shi Houguang |
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| Rok vydání: | 2019 |
| Předmět: |
Drug
Hepatitis B virus media_common.quotation_subject Crystallography X-Ray Antiviral Agents 01 natural sciences Structure-Activity Relationship 03 medical and health sciences Capsid Drug Discovery Hepatitis B virus HBV Animals Cytochrome P-450 CYP3A Humans Structure–activity relationship Cytochrome P-450 CYP2B6 Inducers 030304 developmental biology media_common Mice Inbred BALB C 0303 health sciences Dose-Response Relationship Drug CYP3A4 Chemistry Cytochrome P-450 CYP1A2 Inducers Pregnane X Receptor Cytochrome P-450 CYP3A Inducers Virology Rats 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme Induction Hepatocytes Molecular Medicine Female |
| Zdroj: | Journal of Medicinal Chemistry. 62:10352-10361 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b01421 |
| Popis: | Described herein is a new approach to mitigate CYP3A4 induction. In this unconventional approach, a fine-tuning of the dihedral angle between the C4 phenyl and the dihydropyrimidine core of the heteroaryldihydropyrimidine (HAP) class of capsid inhibitors successfully altered the structure-activity-relationships (SARs) of the unwanted CYP3A4 induction and the desired HBV capsid inhibition to more favorable values. This eventually led to the discovery of a new capsid inhibitor with significantly reduced CYP3A4 induction, excellent anti-HBV activity, favorable preclinical PK/PD profiles, and no early safety flags. |
| Databáze: | OpenAIRE |
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