- 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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- 2,4-Diamino-8-quinazoline carboxamides as novel, potent inhibitors of the NAD hydrolyzing enzyme CD38: Exploration of the 2-position structure-activity relationships
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Starting from 4-amino-8-quinoline carboxamide lead 1a and scaffold hopping to the chemically more tractable quinazoline, a systematic exploration of the 2-substituents of the quinazoline ring, utilizing structure activity relationships and conformational constraint, resulted in the identification of 39 novel CD38 inhibitors. Eight of these analogs were 10–100-fold more potent human CD38 inhibitors, including the single digit nanomolar inhibitor 1am. Several of these molecules also exhibited improved therapeutic indices relative to hERG activity. A representative analog 1r exhibited suitable pharmacokinetic parameters for in vivo animal studies, including moderate clearance and good oral bioavailability. These inhibitor compounds will aid in the exploration of the enzymatic functions of CD38, as well as furthering the study of the therapeutic implications of NAD enhancement in metabolic disease models.
- Deaton, David N.,Haffner, Curt D.,Henke, Brad R.,Jeune, Michael R.,Shearer, Barry G.,Stewart, Eugene L.,Stuart, J. Darren,Ulrich, John C.
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p. 2107 - 2150
(2018/03/28)
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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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