Design, Synthesis, and Evaluation of Tetrahydropyrrolo[1,2- c]pyrimidines as Capsid Assembly Inhibitors for HBV Treatment

Xiaolin Li; Kai Zhou; Haiying He; Qiong Zhou; Ya Sun; Lijuan Hou; Liang Shen; Xiaofei Wang; Yuedong Zhou; Zhen Gong; Shibo He; Huangtao Jin; Zhengxian Gu; Shuyong Zhao; Long Zhang; Chunyan Sun; Shansong Zheng; Zhe Cheng; Yidong Zhu; Minghui Zhang; Jian Li; Shuhui Chen

doi:10.1021/acsmedchemlett.7b00288

Design, Synthesis, and Evaluation of Tetrahydropyrrolo[1,2- c]pyrimidines as Capsid Assembly Inhibitors for HBV Treatment

ACS Med Chem Lett. 2017 Aug 24;8(9):969-974. doi: 10.1021/acsmedchemlett.7b00288. eCollection 2017 Sep 14.

Authors

Xiaolin Li¹, Kai Zhou¹, Haiying He¹, Qiong Zhou¹, Ya Sun¹, Lijuan Hou¹, Liang Shen¹, Xiaofei Wang¹, Yuedong Zhou¹, Zhen Gong¹, Shibo He¹, Huangtao Jin¹, Zhengxian Gu¹, Shuyong Zhao², Long Zhang², Chunyan Sun², Shansong Zheng², Zhe Cheng², Yidong Zhu², Minghui Zhang², Jian Li¹, Shuhui Chen¹

Affiliations

¹ WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China.
² Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co., Ltd., No. 243 Gong Ye Bei Road, Jinan, Shandong Province 250100, P. R. China.

Abstract

The discovery of novel tetrahydropyrrolo[1,2-c]pyrimidines derivatives from Bay41_4109 as hepatitis B virus (HBV) inhibitors is herein reported. The structure-activity relationship optimization led to one highly efficacious compound 28a (IC₅₀ = 10 nM) with good PK profiles and the favorite L/P ratio. The hydrodynamic injection model in mice clearly demonstrated the efficacy of 28a against HBV replication.

Keywords: Hepatitis B virus (HBV); capsid assembly inhibitor; tetrahydropyrrolo[1,2-c]pyrimidines.