- Discovery and Biological Evaluation of N-Methyl-pyrrolo[2,3- b]pyridine-5-carboxamide Derivatives as JAK1-Selective Inhibitors
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Janus kinase 1 (JAK1) plays a key role in most cytokine-mediated inflammatory and autoimmune responses through JAK/STAT signaling; thus, JAK1 inhibition is a promising therapeutic strategy for several diseases. Analysis of the binding modes of current JAK inhibitors to JAK isoforms allowed the design of N-alkyl-substituted 1-H-pyrrolo[2,3-b] pyridine carboxamide as a JAK1-selective scaffold, and the synthesis of various methyl amide derivatives provided 4-((cis-1-(4-chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31g) as a potent JAK1-selective inhibitor. In particular, the (S,S)-enantiomer of 31g (38a) exhibited excellent potency for JAK1 and selectivity over JAK2, JAK3, and TYK2. On investigating the effect of 31g on hepatic fibrosis, it was found that it reduces the proliferation and fibrogenic gene expression of TGF-β-induced hepatic stellate cells (HSCs). Specifically, 31g significantly inhibited TGF-β-induced migration of HSCs at 0.25 μM in wound-healing assays.
- Park, Eunsun,Lee, Sun Joo,Moon, Heegyum,Park, Jongmi,Jeon, Hyeonho,Hwang, Ji Sun,Hwang, Hayoung,Hong, Ki Bum,Han, Seung-Hee,Choi, Sun,Kang, Soosung
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p. 958 - 979
(2021/02/01)
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- Design, synthesis, in vitro and in vivo evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer’s disease
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Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer’s disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, 15b and 15j showed submicromolar IC50 values (15b, eeAChE IC50 = 0.39 ± 0.11 μM; 15j, eqBChE IC50 = 0.16 ± 0.04 μM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that 15b and 15j act in a competitive manner. 15b and 15j showed neuroprotective effect against H2O2-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay in vitro. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of 15b and 15j was lower than tacrine. In summary, these data suggest 15b and 15j are promising multifunctional agents against AD.
- Mo, Jun,Chen, Tingkai,Yang, Hongyu,Guo, Yan,Li, Qi,Qiao, Yuting,Lin, Hongzhi,Feng, Feng,Liu, Wenyuan,Chen, Yao,Liu, Zongliang,Sun, Haopeng
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p. 330 - 343
(2019/12/30)
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