Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors

Bioorg Med Chem Lett. 2020 Oct 15;30(20):127479. doi: 10.1016/j.bmcl.2020.127479.

Ning-Yu Wang ¹, Wei-Qiong Zuo ², Rong Hu ³, Wan-Li Wang ³, Yong-Xia Zhu ², Ying Xu ², Luo-Ting Yu ², Zhi-Hao Liu ⁴

Affiliations

1 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China. Electronic address: wangny-swjtu@swjtu.edu.cn.
2 Lab of Medicinal Chemistry, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
3 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China.
4 Lab of Medicinal Chemistry, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China. Electronic address: liuzhihao@scu.edu.cn.

PMID: 32784091 DOI: 10.1016/j.bmcl.2020.127479

Abstract

Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.

Keywords

Antiproliferative activity; PI3Kδ; Piperazinone; SAR; Thieno[3,2-d]pyrimidine.

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