Design, synthesis and evaluation of novel 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as potent, selective and reversible Bruton's tyrosine kinase (BTK) inhibitors for the treatment of rheumatoid arthritis

Chufeng Zhang; Heying Pei; Jun He; Jiali Zhu; Weimin Li; Ting Niu; Mingli Xiang; Lijuan Chen

doi:10.1016/j.ejmech.2019.02.077

Design, synthesis and evaluation of novel 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as potent, selective and reversible Bruton's tyrosine kinase (BTK) inhibitors for the treatment of rheumatoid arthritis

Eur J Med Chem. 2019 May 1:169:121-143. doi: 10.1016/j.ejmech.2019.02.077. Epub 2019 Mar 6.

Authors

Chufeng Zhang¹, Heying Pei¹, Jun He¹, Jiali Zhu¹, Weimin Li², Ting Niu³, Mingli Xiang⁴, Lijuan Chen⁵

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China.
² Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
³ Department of Hematology and Research Laboratory of Hematology, West China Hospital of Sichuan University, Chengdu, China.
⁴ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China. Electronic address: xiang_mingli@scu.edu.cn.
⁵ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China. Electronic address: chenlijuan125@163.com.

PMID: 30875504
DOI: 10.1016/j.ejmech.2019.02.077

Abstract

A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized as reversible BTK inhibitors, and evaluated their kinase selectivity, anti-proliferation against the B-cell lymphoma cell lines (Ramos, Jeko-1) and cell line BTK enhanced (Daudi) in vitro. Among them, compound 28a exhibited the most excellent potency (IC₅₀ = 3.0 nM against BTK enzyme, 8.52 μM, 11.10 μM and 7.04 μM against Ramos, Jeko-1, Daudi cells, respectively), good kinase selectivity and inhibited BTK Y223 auto-phosphorylation and PLCγ2 Tyr1217 phosphorylation. Importantly, 28a showed efficacy anti-arthritic effect on collagen-induced arthritis (CIA) model in vivo. 28a 60 mg/kg dose level once a day group displayed markedly reduced joint damage and cellular infiltration without any bone and cartilage morphology change.

Keywords: BTK; Inhibitor; Reversible; Rheumatoid arthritis.

MeSH terms

Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
Agammaglobulinaemia Tyrosine Kinase / metabolism
Animals
Arthritis, Experimental / chemically induced
Arthritis, Experimental / drug therapy*
Arthritis, Experimental / metabolism
Arthritis, Rheumatoid / chemically induced
Arthritis, Rheumatoid / drug therapy*
Arthritis, Rheumatoid / metabolism
Collagen
Dose-Response Relationship, Drug
Drug Design*
Humans
Male
Mice
Mice, Inbred DBA
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship

Substances

7H-pyrrolo(2,3-d)pyrimidin-4-amine
Protein Kinase Inhibitors
Pyrimidines
Pyrroles
Collagen
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human