- N-(1H-IMIDAZOL-2-YL)BENZAMIDE COMPOUND AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME AS ACTIVE INGREDIENT
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N-(1H-imidazol-2-yl)benzamide compound of formula (I), or a pharmaceutically acceptable salt, a prodrug, a solvate, or a stereoisomer thereof which is a novel compound exhibiting excellent inhibitory activity against IRAK-4, can be used without side effects for efficient prevention and treatment of diseases mediated by IRAK-4 receptors, particularly autoimmune diseases or lymphomas.
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Page/Page column 41
(2021/04/10)
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- Discovery of acylsulfonohydrazide-derived inhibitors of the lysine acetyltransferase, kat6a, as potent senescence-inducing anti-cancer agents
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A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.
- Priebbenow, Daniel L.,Leaver, David J.,Nguyen, Nghi,Cleary, Benjamin,Lagiakos, H. Rachel,Sanchez, Julie,Xue, Lian,Huang, Fei,Sun, Yuxin,Mujumdar, Prashant,Mudududdla, Ramesh,Varghese, Swapna,Teguh, Silvia,Charman, Susan A.,White, Karen L.,Shackleford, David M.,Katneni, Kasiram,Cuellar, Matthew,Strasser, Jessica M.,Dahlin, Jayme L.,Walters, Michael A.,Street, Ian P.,Monahan, Brendon J.,Jarman, Kate E.,Jousset Sabroux, Helene,Falk, Hendrik,Chung, Matthew C.,Hermans, Stefan J.,Downer, Natalie L.,Parker, Michael W.,Voss, Anne K.,Thomas, Tim,Baell, Jonathan B.
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p. 4655 - 4684
(2020/06/08)
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- Design, synthesis, and biological evaluation of tetrahydroquinolin derivatives as potent inhibitors of CBP bromodomain
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CREB-binding protein (CBP) is a large multi-domain protein containing a HAT domain catalyzing transacetylation and a bromodomain responsible for acetylated lysine recognition. CBPs could act as transcription co-activators to regulate gene expression and have been shown to play a significant role in the development and progression of many cancers. Herein, through in silico screening two hit compounds with tetrahydroquinolin methyl carbamate scaffold were discovered, among which DC-CPin7 showed an in vitro inhibitory activity with the TR-FRET IC50 value of 2.5 ± 0.3 μM. We obtained a high-resolution co-crystal structure of the CBP bromodomain in complex with DC-CPin7 to guide following structure-based rational drug design, which yielded over ten DC-CPin7 derivatives with much higher potency, among which DC-CPin711 showed approximately 40-fold potency compared with hit compound DC-CPin7 with an in vitro TR-FRET IC50 value of 63.3 ± 4.0 nM. Notably, DC-CPin711 showed over 150-fold selectivity against BRD4 bromodomains. Moreover, DC-CPin711 showed micromolar level of anti-leukemia proliferation through G1 phase cell cycle arrest and cell apoptosis. In summary, through a combination of computational and crystal-based structure optimization, DC-CPin711 showed potent in vitro inhibitory activities to CBP bromodomain with a decent selectivity towards BRD4 bromodomains and good cellular activity to leukemia cells, which could further be applied to related biological and translational studies as well as serve as a lead compound for future development of potent and selective CBP bromodomain inhibitors.
- Bi, Xiaoyang,Chen, Kaixian,Chen, Yu,Ding, Hong,Jiang, Hao,Jiang, Hualiang,Lu, Tian,Lu, Wenchao,Luo, Cheng,Sun, Zhongya,Xu, Pan,Zhang, Fengcai,Zhang, Naixia,Zhou, Bing
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supporting information
(2020/06/21)
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- A focused fragment library targeting the antibiotic resistance enzyme - Oxacillinase-48: Synthesis, structural evaluation and inhibitor design
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β-Lactam antibiotics are of utmost importance when treating bacterial infections in the medical community. However, currently their utility is threatened by the emergence and spread of β-lactam resistance. The most prevalent resistance mechanism to β-lactam antibiotics is expression of β-lactamase enzymes. One way to overcome resistance caused by β-lactamases, is the development of β-lactamase inhibitors and today several β-lactamase inhibitors e.g. avibactam, are approved in the clinic. Our focus is the oxacillinase-48 (OXA-48), an enzyme reported to spread rapidly across the world and commonly identified in Escherichia coli and Klebsiella pneumoniae. To guide inhibitor design, we used diversely substituted 3-aryl and 3-heteroaryl benzoic acids to probe the active site of OXA-48 for useful enzyme-inhibitor interactions. In the presented study, a focused fragment library containing 49 3-substituted benzoic acid derivatives were synthesised and biochemically characterized. Based on crystallographic data from 33 fragment-enzyme complexes, the fragments could be classified into R1 or R2 binders by their overall binding conformation in relation to the binding of the R1 and R2 side groups of imipenem. Moreover, binding interactions attractive for future inhibitor design were found and their usefulness explored by the rational design and evaluation of merged inhibitors from orthogonally binding fragments. The best inhibitors among the resulting 3,5-disubstituted benzoic acids showed inhibitory potential in the low micromolar range (IC50 = 2.9 μM). For these inhibitors, the complex X-ray structures revealed non-covalent binding to Arg250, Arg214 and Tyr211 in the active site and the interactions observed with the mono-substituted fragments were also identified in the merged structures.
- Akhter, Sundus,Lund, Bjarte Aarmo,Ismael, Aya,Langer, Manuel,Isaksson, Johan,Christopeit, Tony,Leiros, Hanna-Kirsti S.,Bayer, Annette
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supporting information
p. 634 - 648
(2018/01/19)
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- ARYL SULFONOHYDRAZIDES
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Compound of formula (I) wherein A is selected from (i), where RF1 is H or F; (ii); (iii) a N-containing C6 heteroaryl group; and B is (B), where X1 is either CRF2 or N, where RF2 is H or F; X2 is either CR3 or N, where R3 is selected from H, Me, CI, F OMe; X3 is either CH or N; X4 is either CRF3 or N, where RF3 is H or F; where only one or two of X1, X2, X3 and X4 may be N; and R4 is selected from I, optionally substituted phenyl, optionally substituted C5-6 heteroaryl; optionally substituted C1-6 aIkyI and optionally substituted C1-6 alkoxy, which are useful in the treatment of a condition ameliorated by the inhibition of MOZ.
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Page/Page column 40; 50
(2016/12/26)
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- Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666
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The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor in vitro clearance to yield in vivo tool compound EPZ015666 and an additional potent in vitro tool molecule EPZ015866 (GSK3203591).
- Duncan, Kenneth W.,Rioux, Nathalie,Boriack-Sjodin, P. Ann,Munchhof, Michael J.,Reiter, Lawrence A.,Majer, Christina R.,Jin, Lei,Johnston, L. Danielle,Chan-Penebre, Elayne,Kuplast, Kristy G.,Porter Scott, Margaret,Pollock, Roy M.,Waters, Nigel J.,Smith, Jesse J.,Moyer, Mikel P.,Copeland, Robert A.,Chesworth, Richard
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p. 162 - 166
(2016/03/01)
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- 2-catalyzed directed N -Boc amidation of arenes "on water"
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Rhodium(III) catalysis "on water" is effective for directed C-H amidation of arenes. The catalytic process is promoted by OH groups present on the hydrophobic water surface and is inefficient in all (most) common organic solvents investigated so far. In the presence of easily prepared tert-butyl 2,4-dinitrophenoxycarbamate, a new and stable nitrene source, the "on water" reaction can efficiently provide the desired N-Boc-aminated products with good functional group tolerance.
- Ali, Md Ashif,Yao, Xiayin,Sun, Hao,Lu, Hongjian
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p. 1513 - 1516
(2015/03/30)
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- PRMT5 INHIBITORS AND USES THEREOF
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Described herein are compounds of formula (A), pharmaceutically acceptable salts thereof, and pharmaceutical com-positions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.
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- NCN palladium pincer via transmercuration. Synthesis of [2-(2-oxazoliny)-6-(2-pyridyl)] phenylpalladium(II) chloride and its catalytic activity in Suzuki coupling
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The unsymmetrical NCN ligand 1-(2-oxazolinyl)-3-(2-pyridyl)benzene 6 was synthesized starting from m-bromotoluene after a series of transformations. The reaction of 6 and mercury (II) acetate resulted in mercurial derivative 7 which was transformed into the corresponding NCN palladium pincer 8 via transmercuration. The ultraviolet spectra of 6-8 in acetonitrile were also studied. The structures of 6 and 8 were further confirmed by X-ray single crystal diffraction. The carbon-carbon cross coupling reactions between aryl halides and phenylboronic acid catalyzed by 8 were investigated. The results indicate that this palladium pincer is more highly active to the coupling of aryl bromides than aryl chlorides.
- Li, Ping,Zhou, Hai-Feng,Liu, Fang,Hu, Zhao-Xia,Wang, Hong-Xing
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- BENZOXAZOLE CARBOXAMIDE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP)
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A compound having the structure set forth in Formula (I) or Formula (II): wherein the variables Y, R1, R2, R3, and R4 are as defined herein. Provided herein are inhibitors of poly(ADP-ribose)polymerase activity. Also described herein are pharmaceutical compositions that include at least one compound described herein and the use of a compound or pharmaceutical composition described herein to treat diseases, disorders and conditions that are ameliorated by the inhibition of PARP activity.
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Page/Page column 75
(2009/08/16)
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- Certain pyrazoline derivatives with kinase inhibitory activity
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The present invention provides certain pyrazoline compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutical compositions and methods of using the compositions in the treatment of various diseases.
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Page/Page column 95
(2008/12/06)
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