- Discovery of pyrazole derivatives as cellular active inhibitors of histone lysine specific demethylase 5B (KDM5B/JARID1B)
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KDM5B (also known as PLU-1 and JARID1B) is 2-oxoglutarate and Fe2+ dependent oxygenase that acts as a histone H3K4 demethylase, which is a key participant in inhibiting the expression of tumor suppressors as a drug target. Here, we present the discovery of pyrazole derivatives compound 5 by structure-based virtual screening and biochemical screening with IC50 of 9.320 μM against KDM5B, and its subsequent optimization to give 1-(4-methoxyphenyl)-N-(2-methyl-2-morpholinopropyl)-3-phenyl-1H-pyrazole-4-carboxamide (27 ab), a potent KDM5B inhibitor with IC50 of 0.0244 μM. In MKN45 cells, compound 27 ab can bind and stabilize KDM5B and induce the accumulation of H3K4me2/3, bona fide substrates of KDM5B, while keep the amount of H3K4me1, H3K9me2/3 and H3K27me2 without change. Further biological study also indicated that compound 27 ab is a potent cellular active KDM5B inhibitor that can inhibit MKN45 cell proliferation, wound healing and migration. In sum, our finding gives a novel structure for the discovery of KDM5B inhibitor and targeting KDM5B may be a new therapeutic strategy for gastric cancer treatment.
- Liang, Qianqian,Liu, Hong-Min,Ma, Li-Ying,Ren, Hongmei,Wu, Yang,Zhang, Kun,Zhang, Xinhui,Zhao, Bing,Zheng, Yi-Chao
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- NOVEL IMIDAZOLE COMPOUND AND USE THEREOF AS MELANOCORTIN RECEPTOR AGONIST
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The present invention relates to a novel imidazole compound or a pharmaceutically acceptable salt thereof having a melanocortin receptor agonistic activity, and medical use thereof. The present invention relates to an imidazole compound represented by general formula [I] [wherein: Ring A represents an optionally substituted aryl group or the like; R1 represents a hydrogen atom, an optionally substituted alkyl group, or the like; R2 represents a hydrogen atom, a halogen atom, or the like; and R3 represents an optionally substituted alkyl group] or a pharmaceutically acceptable salt thereof.
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Paragraph 0520
(2018/10/04)
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- Pharmaceutical compositions (by machine translation)
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[Problem] imidazole compound or its pharmacologically acceptable salt in the melanocortin receptor activity that operates as an active ingredient of a pharmaceutical composition comprising. "I" general formula [a]" Formula, the aryl group may be substituted A ring represents a; R1 Represents a hydrogen atom, or an alkyl group which may be substituted represented; R2 Represents a hydrogen atom, a halogen atom or represents a; R3 The alkyl group may be substituted " represented by the imidazole compound, its pharmacologically acceptable salt as an active ingredient in a pharmaceutical composition. [Drawing] no (by machine translation)
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Paragraph 0191
(2019/01/31)
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- Nafion-Fe: A new efficient "green" lewis acid catalyst for the ketonic strecker reaction
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The synthesis of various α-aminonitriles, precursors of α-amino acids has been carried out in moderate to high yields and high purity by the Strecker reaction from ketones, aliphatic/aromatic amines and TMSCN using a new "green" Lewis acid catalyst, Nafion-Fe (iron Nafionate, Fe(III) salt of Nafion-H, a solid polymeric perfluoroalkanesulfonic acid) under conventional thermal as well as microwave conditions. Microwave and solvent-free conditions applied in this method shorten the reaction times, improve the yields and diminishes the formation of side products. Strecker reaction occurs smoothly with secondary aliphatic amines also under these conditions which is not common under conventional conditions.
- Surya Prakash,Bychinskaya, Inessa,Marinez, Eric R.,Mathew, Thomas,Olah, George A.
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p. 303 - 312
(2013/05/09)
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- New morpholine analogues of phencyclidine: Chemical synthesis and pain perception in rats
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Phencyclidine (PCP, I) and most its derivatives have demonstrated some pharmacological effects. Accordingly, in this study, the new methoxy (III) and hydroxy-methyl (IV) morpholine PCP derivatives were synthesized. The acute and chronic pain activities of these drugs (III, IV) were investigated by tail immersion and formalin tests on rats and the results were compared with those in PCP, PCM (PCP-morpholine, II), and methyl-PCM (V). Findings indicated that III (6 mg/kg, i.p.) generates more analgesic effects in tail immersion test in comparison with I and II in 20, 40, 45 and 55 min post-injection. These effects were observed in 10, 20, 40, 45 and 50 min after the application of IV (at the same dosage). This analgesic effect was markedly seen in 20, 40, 45 and 50 min after compound IVs application in comparison with the drugs (I-V). In formalin test analysis, the acute chemical pain (Phase I) could not be affected by any drugs (I-V) while chronic formalin pain would be diminished by these new synthesized drugs (III and IV), especially in late Phase II, compared to I and II at the dosage of 6 mg/kg. It is, therefore, concluded that these new synthesized PCP derivates including methoxy-PCM (III) and hydroxy-methyl-PCM (IV) could substantially and respectively diminish acute thermal and chronic chemical pains.
- Ahmadi, Abbas,Khalili, Mohsen,Hajikhani, Ramin,Naserbakht, Moslem
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p. 227 - 233
(2013/01/09)
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- Heterogeneously catalysed Strecker-type reactions using supported Co(ii) catalysts: Microwave vs. conventional heating
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A range of α-aminonitriles could be efficiently prepared from various aldehydes/ketones and primary or secondary amines using a highly active and stable Co(ii) complex supported on different mesoporous supports at both room temperature and low temperature microwave irradiation under solventless conditions. Catalysts were also highly reusable under the investigated reaction conditions and could be reused at least 10 times without loss of catalytic activity. The Royal Society of Chemistry.
- Rajabi, Fatemeh,Nourian, Saghar,Ghiassian, Sara,Balu, Alina M.,Saidi, Mohammad Reza,Serrano-Ruiz, Juan Carlos,Luque, Rafael
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experimental part
p. 3282 - 3289
(2011/12/15)
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- Discovery of a novel series of selective HCN1 blockers
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The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4- isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.
- McClure, Kelly J.,Maher, Michael,Wu, Nancy,Chaplan, Sandra R.,Eckert III, William A.,Lee, Dong H.,Wickenden, Alan D.,Hermann, Michelle,Allison, Brett,Hawryluk, Natalie,Breitenbucher, J. Guy,Grice, Cheryl A.
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scheme or table
p. 5197 - 5201
(2011/10/02)
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- Efficient Co(ii) heterogeneously catalysed synthesis of α-aminonitriles at room temperature via Strecker-type reactions
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An environmentally friendly and highly active mesoporous Co(ii) complex on mesoporous SBA-15 material could be used as an easily recoverable catalyst for the synthesis of α-aminonitriles from a wide range of aldehydes/ketones and primary or secondary amines with good to excellent conversions yields at room temperature under solventless conditions. The catalyst can be recovered by simple filtration and could be reused at least 10 times without loss of catalytic activity.
- Rajabi, Fatemeh,Ghiassian, Sara,Saidi, Mohammad Reza
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supporting information; experimental part
p. 1349 - 1352
(2010/09/15)
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- Bis(dialkylamino)cyanoboranes: Highly efficient reagents for the Strecker-type aminative cyanation of aldehydes and ketones
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a-Dialkylamino nitriles are formed in excellent yields in the reactions of bis(dialkylamino)cyanoboranes with a wide array of carbonyl compounds.
- Suginome, Michinori,Yamamoto, Akihiko,Ito, Yoshihiko
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p. 1392 - 1393
(2007/10/03)
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- A facile method for preparing aminobicyclo[n.1.0]alkane derivatives
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The action of iodine on enamine (1) in the presence of anions, such as methoxide, cyanide, or succinimide ion, in methanol brings about an intramolecular cyclization and simultaneous substitution with these anions to give the corresponding aminobicyclo[n.1.0]alkane derivatives (2-4) in good yields.
- Chiba, Toshiro,Saitoh, Isao,Okimoto, Mitsuhiro
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p. 1022 - 1026
(2007/10/03)
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- Effect of lowered lipophilicity on the affinity of PCP analogues for the PCP receptor and the dopamine transporter
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Oxygen and sulphur atoms were introduced in the cyclohexyl and piperidinyl moieties of the basic structures 1-(1-phenyl-cyclohexyl)piperidine (PCP), 1- [1-(2-thienyl)cyclohexyl]piperidine (TCP), and 1-[1-(2- benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP) to lower their global lipophilicity. The compounds obtained were tested comparatively for their affinity for the PCP receptor labelled with [3H]TCP and for the dopamine (DA) transporter labelled with [3H]BTCP. Lowering the global lipophilicity in PCP and TCP series is detrimental to the affinity and selectivity for the PCP receptor. In the BTCP series lowering of the global lipophilicity is less deleterious and may, on the contrary, be a useful way of increasing selectivity for the DA transporter in some instances.
- Hamon,Vignon,Kamenka
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p. 489 - 495
(2007/10/03)
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