- 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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- 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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- Synthesis, structure-activity relationship studies, and identification of novel 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as dual orexin receptor antagonists. Part 1
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A novel series of non-peptidic OX1R/OX2R orexin receptor antagonists was prepared by heterocyclic replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of almorexant. Introduction of substituted imidazole moieties delivered potent dual orexin receptor antagonists with nanomolar potency for hOX1R and hOX2R suitable for further fine-tuning. The preparation of these novel orexin receptor antagonists and the outcome of preliminary structure-activity relationship studies are described in this communication.
- Sifferlen, Thierry,Koberstein, Ralf,Cottreel, Emmanuelle,Boller, Amandine,Weller, Thomas,Gatfield, John,Brisbare-Roch, Catherine,Jenck, Francois,Boss, Christoph
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p. 2212 - 2216
(2013/04/23)
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- QUINOLONES USEFUL AS INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITORS
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The present invention relates to novel quinolones of Formula I that inhibit inducible NOS synthase together with methods of synthesizing and using the compounds including methods for inhibiting or modulating nitric oxide synthesis and/or lowering nitric oxide levels in a patient by administering the compounds for the treatment of disease.
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Page/Page column 108
(2008/12/06)
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- MANUFACTURING METHOD OF 2-SUBSTITUTED IMIDAZOLE COMPOUND
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PROBLEM TO BE SOLVED: To provide a high-yield manufacturing method of a 2-substituted imidazole which is expected to be useful as a curing agent for epoxy resins, polyurethane resins or the like, as an intermediate of various agrochemicals, antibiotics or pharmaceuticals such as anti-AIDS agents or the like, or as dye intermediates. SOLUTION: An aldehyde compound is reacted with ammonia (I) to give an imine compound, and subsequently an α,β-dicarbonyl compound and ammonia (II) are added and allowed to react with the imine compound. Preferably, the α,β-dicarbonyl compound and ammonia (II) are simultaneously added.
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Page/Page column 4-5
(2010/02/11)
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- Tetrasubstituted imidazoles
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A compound of the formula STR1 wherein the substituents are defined in the specification useful for the treatment of cardiovascular disorders.
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- Method of preventing abnormal stimulation of AT1 and AT2 receptors
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Products of formula (1), wherein R1 is particularly STR1 alkyl, alkylthio or alkoxy; R2 is particularly halogen, --S--R, --O--R or --C(OH)(R)--COOH, where R is alkyl or alkenyl; R3 is particularly carboxy, acyl, halogen, alkyl, alkenyl or alkylthio; and R4 is particularly --(CH2)m1 --COOR4, --(CH2)m1 --CONHR14, --(CH2)m1 --CN, --SO2 --NH--SO2 --R14, 13 NH--SO2 --R14, --PO3 R14, or --NH--SO2 --CF3, where m1 is 0-4 and R14 is hydrogen, alkyl or alkenyl; are useful for preparing pharmaceutical compositions for treating disorders resulting from abnormal stimulation of angiotensin II receptors AT1 and AT2.
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