A New Approach of Mitigating CYP3A4 Induction Led to the Discovery of Potent Hepatitis B Virus (HBV) Capsid Inhibitor with Optimal ADMET Profiles.
Identifieur interne : 000B94 ( Main/Exploration ); précédent : 000B93; suivant : 000B95A New Approach of Mitigating CYP3A4 Induction Led to the Discovery of Potent Hepatitis B Virus (HBV) Capsid Inhibitor with Optimal ADMET Profiles.
Auteurs : Xianfeng Lin ; Houguang Shi ; Weixing Zhang ; Zongxing Qiu ; Zheng Zhou ; Fabian Dey ; Sheng Zhong ; Hongxia Qiu ; Jianxun Xie ; Xue Zhou ; Guang Yang ; Guozhi Tang ; Hong C. Shen ; Wei ZhuSource :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2019.
Abstract
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.
DOI: 10.1021/acs.jmedchem.9b01421
PubMed: 31689116
Affiliations:
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