- Design, synthesis, biological evaluation and pharmacophore model analysis of novel tetrahydropyrrolo[3,4-c]pyrazol derivatives as potential TRKs inhibitors
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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.
- Cheng, Maosheng,Liu, Nian,Lv, Ruicheng,Qin, Qiaohua,Sun, Yin,Sun, Yixiang,Wang, Ruifeng,Wang, Xiaoyan,Wu, Tianxiao,Yin, Wenbo,Zhang, Chu,Zhao, Dongmei
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- TETRAAZA-CYCLOPENTA[A]INDENYL AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS
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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.
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Page/Page column 80
(2013/07/05)
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- Discovery of pyrroloaminopyrazoles as novel PAK inhibitors
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The P21-activated kinases (PAK) are emerging antitumor therapeutic targets. In this paper, we describe the discovery of potent PAK inhibitors guided by structure-based drug design. In addition, the efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo.
- Guo, Chuangxing,McAlpine, Indrawan,Zhang, Junhu,Knighton, Daniel D.,Kephart, Susan,Johnson, M. Catherine,Li, Haitao,Bouzida, Djamal,Yang, Anle,Dong, Liming,Marakovits, Joseph,Tikhe, Jayashree,Richardson, Paul,Guo, Lisa C.,Kania, Robert,Edwards, Martin P.,Kraynov, Eugenia,Christensen, James,Piraino, Joseph,Lee, Joseph,Dagostino, Eleanor,Del-Carmen, Christine,Deng, Ya-Li,Smeal, Tod,Murray, Brion W.
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experimental part
p. 4728 - 4739
(2012/07/28)
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- Identification of novel pyrrolopyrazoles as protein kinase C β II inhibitors
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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.
- 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
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scheme or table
p. 584 - 587
(2011/02/27)
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- SUBSTITUTED PYRROLO-PYRAZOLE DERIVATIVES AS KINASE INHIBITORS
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Compounds represented by formula (Ia) or (lb) and wherein R and R1 are as defined in the description, and pharmaceutically acceptable salts thereof, are disclosed; the said compounds are useful in the treatment of cell cycle proliferative disor
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- Synthesis of 2,2-Dimethyl-1,2-Dihydro-3H-pyrrol-3-one
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The title cmpound 3g is obtained via two different routes, either in a multistep synthesis starting from 2-amino-2-methylpropionic acid (methylalanine) or by light-induced, oxidative dealkylation of the corresponding N-isopropyl derivative 3c.
- Patjens, Jan,Ghaffari-Tabrizi, Ramin,Margaretha, Paul
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p. 905 - 907
(2007/10/02)
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