- Design, synthesis, structure-activity relationships study and X-ray crystallography of 3-substituted-indolin-2-one-5-carboxamide derivatives as PAK4 inhibitors
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We have previously described the identification of indolin-2-one-5-carboxamides as potent PAK4 inhibitors. This study expands the structure-activity relationships on our original series by presenting several modifications in the lead compounds, 2 and 3. A series of novel derivatives was designed, synthesized, and evaluated in biochemical and cellular assay. Most of this series displayed nanomolar biochemical activity and potent antiproliferative activity against A549 and HCT116 cells. The representative compound 10a exhibited excellent enzyme inhibition (PAK4 IC50 = 25 nM) and cellular potency (A549 IC50 = 0.58 μM, HCT116 IC50 = 0.095 μM). An X-ray structure of compound 10a bound to PAK4 was obtained. Crystallographic analysis confirmed predictions from molecular modeling and helped refine SAR results. In addition, Compound 10a displayed focused multi-targeted kinase inhibition, good calculated drug-likeness properties. Further profiling of compound 10a revealed it showed weak inhibitory activity against various isoforms of human cytochrome P450.
- Guo, Jing,Zhao, Fan,Yin, Wenbo,Zhu, Mingyue,Hao, Chenzhou,Pang, Yu,Wu, Tianxiao,Wang, Jian,Zhao, Dongmei,Li, Haitao,Cheng, Maosheng
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p. 197 - 209
(2018/06/12)
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- FUMAGILLOL COMPOUNDS AND METHODS OF MAKING AND USING SAME
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Disclosed herein, in part, are fumagillol compounds and methods of use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making fumagillol compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.
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Paragraph 00205
(2018/03/06)
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- Imidazole-based pinanamine derivatives: Discovery of dual inhibitors of the wild-type and drug-resistant mutant of the influenza A virus
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We previously reported potent hit compound 4 inhibiting the wild-type influenza A virus A/HK/68 (H3N2) and A/M2-S31N mutant viruses A/WS/33 (H1N1), with its latter activity quite weak. To further increase its potency, a structure-activity relationship study of a series of imidazole-linked pinanamine derivatives was conducted by modifying the imidazole ring of this compound. Several compounds of this series inhibited the amantadine-sensitive virus at low micromolar concentrations. Among them, 33 was the most potent compound, which was identified as being active on an amantadine-sensitive virus through blocking of the viral M2 ion channel. Furthermore, 33 markedly inhibited the amantadine-resistant virus (IC50 = 3.4 μM) and its activity increased by almost 24-fold compared to initial compound, with its action mechanism being not M2 channel mediated.
- Dong, Jianghong,Chen, Shengwei,Li, Runfeng,Cui, Wei,Jiang, Haiming,Ling, Yixia,Yang, Zifeng,Hu, Wenhui
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p. 605 - 615
(2015/12/30)
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- LRRK2 INHIBITORS
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Provided herein are compounds that inhibit or partially inhibit the activity of leucine rich repeat kinases. Also provided herein are methods of treatment of CNS disorders comprising administration of inhibitors of leucine rich repeat kinases.
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Page/Page column 112
(2013/02/28)
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- Direct synthesis of pyrroles via a silver-promoted three-component reaction involving unusual imidazole ring opening
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A novel silver-promoted three-component reaction toward the synthesis of multifunctionalized pyrroles has been developed. This reaction involves an unusual imidazole ring decomposition, presumably via 1,5-isomerization and subsequent hydrolysis.
- Zeng, Jing,Bai, Yaguang,Cai, Shuting,Ma, Jimei,Liu, Xue-Wei
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supporting information; experimental part
p. 12855 - 12857
(2012/02/03)
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- 5-Substituted imidazole-4-acetic acid analogues: Synthesis, modeling, and pharmacological characterization of a series of novel γ-aminobutyric acidC receptor agonists
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A series of ring-substituted analogues of imidazole-4-acetic acid (IAA, 4), a partial agonist at both GABAA and GABAC receptors (GABA = γ-aminobutyric acid), have been synthesized. The synthesized compounds 8a-1 have been evaluated a
- Madsen, Christian,Jensen, Anders A.,Liljefors, Tommy,Kristiansen, Uffe,Nielsen, Birgitte,Hansen, Camilla P.,Larsen, Mogens,Ebert, Bjarke,Bang-Andersen, Benny,Krogsgaard-Larsen, Povl,Fr?lund, Bente
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p. 4147 - 4161
(2008/02/13)
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- Synthesis of 4(5)-Acyl-, 1-Substituted 5-Acyl, and 1-Substituted 4-Acyl-1H-imidazoles from 4-Aminoisoxazoles
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4-Aminoisoxazoles can be acylated with a wide variety of activated carboxylic acids.Hydrogenation of the resulting amides gives α-(acylamino)enaminones, which cyclize to 4(5)-acylimidazoles upon treatment with base.This method allows for the synthesis of acylimidazoles with a wide range of substituents at C-2.Utilization of N-substituted 4-aminoisoxazoles in the same sequence of reactions yields 1-substituted 5-acylimidazoles, a substitution pattern not otherwise easily prepared.Treatment of α-(acylamino)enaminones, derived from N-unsubstituted isoxazoles, with primary amines leads to incorporation of the amine at the β-position with concomitant expulsion of ammonia.This sequence efficiently yields 1-substituted and 1,2-disubstituted 4-acylimidazoles but does not give satisfactory yields of 5-substituted 4-acylimidazoles due to steric inhibition of the amine exchange.
- Reiter, Lawrence A.
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p. 2714 - 2726
(2007/10/02)
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- IMIDAZO [1,5-d]-AS-TRIAZINE-4(3H)-ONES AND THIONES
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There is provided substituted imidazo[1,5-d]-as-triazine-4(3H)-ones and substituted imidazo[1,5-d]-as-triazin-4(3H)-thiones useful as inhibitors of the enzyme cyclic-AMP phosphodiesterase and as broad spectrum herbicides
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- Imidazo[1,5-d]-as-triazines
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There are provided novel substituted imidazo-[1,5-d]-as-triazines useful as hypotensive agents as well as exhibiting herbicidal activity.
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- Cyclic aminals of aromatic heterocyclic compounds
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Cyclic aminals of aromatic heterocyclic compounds useful in the dyestuffs, pharmaceutical and pesticides industries, are prepared by reacting aromatic heterocyclic compounds containing at least one NH-group in a ring with a tetra-aminoethylene. The cyclic
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