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.
- 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: [email protected].
- 5. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China. Electronic address: [email protected].
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.