- Design, synthesis and biological activity of bicyclic carboxamide derivatives as TRK inhibitors
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‘precision medicine’ is characterized by the selection of targeted drugs based on genetic characteristics of tumor from patients, and no longer selected basis on the type of cancer tissue. Among them, clinical trials on neurotrophin receptor tyrosine kinase genes (NTRK) have proven that great anti-cancer effects can be achieved in different cancer patients. In this paper, a novel total of twenty compounds in two categories have been designed and synthesized. Results of Kinase activity tests showed that I-9 (TRKA IC50 = 1.3 nM, TRKAG595R IC50 = 6.1 nM), and I-10 (TRKA IC50 = 1.1 nM, TRKAG595R IC50 = 5.3 nM) have significant inhibitory activity, and results of cell viability tests showed that I-9 and I-10 can maintain a great inhibitory effect in the Ba/F3-LMNA-NTRK1 cell line(IC50 = 81.1 nM and 41.7 nM, respectively), and in Ba/F3-LMNA-NTRK1-G595R cell line, I-9 and I-10 have better cell activity (IC50 was 495.3 nM, 336.6 nM, respectively) compared with the positive control drug LOXO-101. These results indicate that I-9 and I-10 are potential TRK inhibitors that can overcome drug resistance for further investigation.
- Cai, Shi,Li, Pei,Sun, Minghao,Zhang, Fangqing,Zhang, Huibin,Zhou, Jinpei
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- Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome
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On the basis of its essential role in driving inflammation and disease pathology, cell necrosis has gradually been verified as a promising therapeutic target for treating atherosclerosis, systemic inflammatory response syndrome (SIRS), and ischemia injury, among other diseases. Most necrosis inhibitors targeting receptor-interacting protein 1 (RIP1) still require further optimization because of weak potency or poor metabolic stability. We conducted a phenotypic screen and identified a micromolar hit with novel amide structure. Medicinal chemistry efforts yielded a highly potent, selective, and metabolically stable drug candidate, compound 56 (RIPA-56). Biochemical studies and molecular docking revealed that RIP1 is the direct target of this new series of type III kinase inhibitors. In the SIRS mice disease model, 56 efficiently reduced tumor necrosis factor alpha (TNFα)-induced mortality and multiorgan damage. Compared to known RIP1 inhibitors, 56 is potent in both human and murine cells, is much more stable in vivo, and is efficacious in animal model studies.
- Ren, Yan,Su, Yaning,Sun, Liming,He, Sudan,Meng, Lingjun,Liao, Daohong,Liu, Xiao,Ma, Yongfen,Liu, Chunyan,Li, Sisi,Ruan, Hanying,Lei, Xiaoguang,Wang, Xiaodong,Zhang, Zhiyuan
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p. 972 - 986
(2017/02/19)
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- 4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors
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Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and associated structure-activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41.
- Pechulis, Anthony D.,Beck, James P.,Curry, Matt A.,Wolf, Mark A.,Harms, Arthur E.,Xi, Ning,Opalka, Chet,Sweet, Mark P.,Yang, Zhicai,Vellekoop, A. Samuel,Klos, Andrew M.,Crocker, Peter J.,Hassler, Carla,Laws, Mia,Kitchen, Douglas B.,Smith, Mark A.,Olson, Richard E.,Liu, Shuang,Molino, Bruce F.
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p. 7219 - 7222
(2013/01/15)
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- Antimycobacterial activity of new 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-one derivatives. Molecular modeling investigations
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3H-1,3,4-Oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the reference strain of Mycobacterium tuberculosis H37Rv. Molecular modeling investigations were performed and showed that the active compounds possess all necessary features to target the protein active site of the mycobacterial cytochrome P450-dependent sterol 14α-demethylase in the sterol biosynthesis pathway as the calculated free energy of binding were in agreement with the corresponding MIC values.
- Zampieri, Daniele,Mamolo, Maria Grazia,Laurini, Erik,Fermeglia, Maurizio,Posocco, Paola,Pricl, Sabrina,Banfi, Elena,Scialino, Giuditta,Vio, Luciano
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experimental part
p. 4693 - 4707
(2009/10/24)
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- 4-Phenyl substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin
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The present invention relates to a method of treating disorders by administering a compound of the formulae IA-IF. These compounds are tetrahydroisoquinolines of the following structure: wherein R1-R8 for compounds of each of the formulae IA, IB, IC, ID, IE and IF are as described herein.
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Page/Page column 26-27
(2010/11/08)
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- TACHYKININ RECEPTOR ANTAGONISTS
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The present invention relates to selective NK-1 receptor antagonists of Formula (I) or a pharmaceutically acceptable salt thereof, for the treatment of disorders associated with an excess of tachykinins.
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- Benzylamines: Synthesis and evaluation of antimycobacterial properties
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The synthesis of benzylamines with various N-alkyl chains and substituents in the aromatic system as well as their evaluation on Mycobacterium tuberculosis H 37 Ra are described. The most active compounds in this test, N-methyl-3-chlorobenzylamine (MIC 10.2 μg/mL), N-methyl-3,5-dichlorobenzylamine (93, MIC 10.2 μg/mL), and N-butyl-3,5-difluorobenzylamine (MIC 6.4 μg/mL), also exhibited a marked inhibitory effect on Mycobacterium marinum and Mycobacterium lufu used for the determination of antileprotic properties. The combination of 93 with aminosalicylic acid, streptomycin, or dapsone exert marked supra-additive effects on M. tuberculosis H 37 Ra.
- Meindl,Von Angerer,Schonenberger,Ruckdeschel
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p. 1111 - 1118
(2007/10/02)
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