718632-40-7Relevant articles and documents
Design, synthesis, biological evaluation and pharmacophore model analysis of novel tetrahydropyrrolo[3,4-c]pyrazol derivatives as potential TRKs inhibitors
Cheng, Maosheng,Liu, Nian,Lv, Ruicheng,Qin, Qiaohua,Sun, Yin,Sun, Yixiang,Wang, Ruifeng,Wang, Xiaoyan,Wu, Tianxiao,Yin, Wenbo,Zhang, Chu,Zhao, Dongmei
, (2021/06/28)
The tropomyosin receptor kinases TRKs are responsible for different tumor types which caused by NTRK gene fusion, and have been identified as a successful target for anticancer therapeutics. Herein, we report a potent and selectivity TRKs inhibitor 19m through rational drug design strategy from a micromolar potency hit 17a. Compound 19m significantly inhibits the proliferation of TRK-dependent cell lines (Km-12), while it has no inhibitory effect on TRK-independent cell lines (A549 and THLE-2). Furthermore, kinases selectivity profiling showed that in addition to TRKs, compound 19m only displayed relatively strong inhibitory activity on ALK. These data may indicate that compound 19m has a good drug safety. Partial ADME properties were evaluated in vitro and in vivo. Compound 19m exhibited a good AUC values and volume of distribution and low clearance in the pharmacokinetics experiment of rats. Finally, a pharmacophore model guided by experimental results is proposed. We hope this theoretical model can help researchers find type I TRK inhibitors more efficiently.
TETRAAZA-CYCLOPENTA[A]INDENYL AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS
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Page/Page column 81, (2013/07/05)
The present invention provides compounds of Formula (I) as M1 receptor positive allosteric modulators for the treatment of diseases mediated by the muscarinic M1 mediator.
Identification of novel pyrrolopyrazoles as protein kinase C β II inhibitors
Li, Hui,Hong, Yufeng,Nukui, Seiji,Lou, Jihong,Johnson, Sarah,Scales, Stephanie,Botrous, Iriny,Tompkins, Eileen,Yin, Chunfeng,Zhou, Ru,He, Mingying,Jensen, Jordan,Bouzida, Djamal,Alton, Gordon,Lafontaine, Jennifer,Grant, Stephan
scheme or table, p. 584 - 587 (2011/02/27)
A novel series of pyrrolopyrazole-based protein kinase C β II inhibitors has been identified from high-throughput screening. Herein, we report our initial structure-activity relationship studies with a focus on optimizing compound ligand efficiency and physicochemical properties, which has led to potent inhibitors with good cell permeability.