7306-68-5Relevant articles and documents
Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis
He, Linhong,Pei, Heying,Lan, Tingxuan,Tang, Minghai,Zhang, Chufeng,Chen, Lijuan
, (2017)
Selective inhibition of Janus kinase 3 (JAK3) has been identified as an important strategy for the treatment of autoimmune disorders. Based on the unique cysteine 909 residue (Cys909) of JAK3 at the gatekeeper position, we have developed a new irreversible covalent inhibitor, III-4, which is highly potent and selective in targeting JAK3. Importantly, III-4 selectively inhibited JAK3 (IC50 = 57 ± 1.21 nM) over other JAKs (IC50 > 10 μM) and Cys909 kinome members (IC50 > 1 μM). A cellular selectivity study also confirmed that III-4 preferentially inhibited JAK3 over JAK1 in JAK/STAT signaling. Moreover, the fact that III-4 covalently modified the Cys909 residue in JAK3 was clearly validated by mass spectrometry and covalent docking analysis. Based on the favorable target profiles, the pharmacokinetic properties and its low toxicity, III-4 exhibited better efficacy than tofacitinib in impeding disease progression in CIA mice, without any significant adverse effects. Taken together, III-4 is a potent, selective, and durable inhibitor of JAK3 and has the potential for the treatment of inflammatory disorders and autoimmune diseases, such as rheumatoid arthritis.
Synthesis and Pharmacological Evaluation of Novel Non-nucleotide Purine Derivatives as P2X7 Antagonists for the Treatment of Neuroinflammation
Calzaferri, Francesco,Narros-Fernández, Paloma,De Pascual, Ricardo,De Diego, Antonio M.G.,Nicke, Annette,Egea, Javier,García, Antonio G.,De Los Ríos, Cristóbal
, p. 2272 - 2290 (2021/03/01)
The ATP-gated P2X7 purinergic receptor (P2X7) is involved in the pathogenesis of many neurodegenerative diseases (NDDs). Several P2X7 antagonists have been developed, though none of them reached clinical trials for this indication. In this work, we designed and synthesized novel blood-brain barrier (BBB)-permeable derivatives as potential P2X7 antagonists. They comprise purine or xanthine cores linked to an aryl group through different short spacers. Compounds were tested in YO-PRO-1 uptake assays and intracellular calcium dynamics in a human P2X7-expressing HEK293 cell line, two-electrode voltage-clamp recordings in Xenopus laevis oocytes, and in interleukin 1β release assays in mouse peritoneal macrophages. BBB permeability was assessed by parallel artificial membrane permeability assays and P-glycoprotein ATPase activity. Dichloroarylpurinylethanones featured a certain P2X7 blockade, being compound 6 (2-(6-chloro-9H-purin-9-yl)-1-(2,4-dichlorophenyl)ethan-1-one), named ITH15004, the most potent, selective, and BBB-permeable antagonist. Compound 6 can be considered as a first non-nucleotide purine hit for future drug optimizations.
TRANSGLUTAMINASE 2 (TG2) INHIBITORS
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Paragraph 00856, (2020/03/02)
Described herein are compounds and pharmaceutical compositions containing such compounds which inhibit transglutaminase 2 (TG2). Also described herein are methods for using such TG2 inhibitors, alone or in combination with other compounds, for treating diseases or conditions that would benefit from TG2 inhibition.
