Synthesis and biological evaluation of novel 1-substituted 3-(3-phenoxyprop-1-yn-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amines as potent Bruton's tyrosine kinase (BTK) inhibitors

Nan Zheng; Qun Hao; Kuaile Lin; Jing Pan; Yingxia Li; Weicheng Zhou

doi:10.1016/j.bmcl.2018.11.051

Synthesis and biological evaluation of novel 1-substituted 3-(3-phenoxyprop-1-yn-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amines as potent Bruton's tyrosine kinase (BTK) inhibitors

Bioorg Med Chem Lett. 2019 Jan 15;29(2):225-229. doi: 10.1016/j.bmcl.2018.11.051. Epub 2018 Nov 27.

Authors

Nan Zheng¹, Qun Hao², Kuaile Lin², Jing Pan¹, Yingxia Li³, Weicheng Zhou⁴

Affiliations

¹ Shanghai Key Lab. of Anti-infectives, State Key Lab. of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
² Shanghai Key Lab. of Anti-infectives, State Key Lab. of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China.
³ School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China. Electronic address: liyx417@fudan.edu.cn.
⁴ Shanghai Key Lab. of Anti-infectives, State Key Lab. of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China. Electronic address: zhouweicheng58@163.com.

PMID: 30522954
DOI: 10.1016/j.bmcl.2018.11.051

Abstract

A new series of 1-substituted pyrazolopyrimidine derivatives were synthesized as potent BTK inhibitors and they were evaluated by enzyme-based assay and anti-proliferation against multiple B-cell lymphoma cell lines in vitro. Among these compounds, 9h exhibited the highest potency against BTK enzyme, with IC₅₀ value of 4.2 nM. In particular, 8 and 9f performed better inhibition against the proliferation of B lymphoma cell lines DOHH2 and WSU-DLCL2 than the clinical drug ibrutinb. In addition, the test toward the normal PBMC cells showed that 8 possessed low cell cytotoxicity. All these explorations indicated that 8 could serve as a valuable anti-tumor agent for B-cell lymphoblastic leukemia treatment.

Keywords: 1-Substituted pyrazolo[3,4-d]pyrimidine; B-cell lymphoblastic leukemia; BTK inhibitors; Cytotoxicity; Inhibitory activity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
Agammaglobulinaemia Tyrosine Kinase / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Leukemia, B-Cell / drug therapy*
Leukemia, B-Cell / metabolism
Leukemia, B-Cell / pathology
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / metabolism
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
Agammaglobulinaemia Tyrosine Kinase