63555-50-0Relevant academic research and scientific papers
SULFONIMIDAMIDE COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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Page/Page column 508, (2020/08/13)
In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: (Formula AA) or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.
Discovery of Selective Inhibitors of Endoplasmic Reticulum Aminopeptidase 1
Maben, Zachary,Arya, Richa,Rane, Digamber,An, W. Frank,Metkar, Shailesh,Hickey, Marc,Bender, Samantha,Ali, Akbar,Nguyen, Tina T.,Evnouchidou, Irini,Schilling, Roger,Stratikos, Efstratios,Golden, Jennifer,Stern, Lawrence J.
, p. 103 - 121 (2020/02/20)
ERAP1 is an endoplasmic reticulum-resident zinc aminopeptidase that plays an important role in the immune system by trimming peptides for loading onto major histocompatibility complex proteins. Here, we report discovery of the first inhibitors selective for ERAP1 over its paralogues ERAP2 and IRAP. Compound 1 (N-(N-(2-(1H-indol-3-yl)ethyl)carbamimidoyl)-2,5-difluorobenzenesulfonamide) and compound 2 (1-(1-(4-acetylpiperazine-1-carbonyl)cyclohexyl)-3-(p-tolyl)urea) are competitive inhibitors of ERAP1 aminopeptidase activity. Compound 3 (4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid) allosterically activates ERAP1's hydrolysis of fluorogenic and chromogenic amino acid substrates but competitively inhibits its activity toward a nonamer peptide representative of physiological substrates. Compounds 2 and 3 inhibit antigen presentation in a cellular assay. Compound 3 displays higher potency for an ERAP1 variant associated with increased risk of autoimmune disease. These inhibitors provide mechanistic insights into the determinants of specificity for ERAP1, ERAP2, and IRAP and offer a new therapeutic approach of specifically inhibiting ERAP1 activity in vivo.
Discovery of trans-3-(pyridin-3-yl)acrylamide-derived sulfamides as potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for the potential treatment of cancer
Zhang, Kuojun,Ni, Yong,Chen, Jiaxuan,Tu, Zhengchao,Wu, Xiaoxing,Chen, Dong,Yao, Hequan,Jiang, Sheng
, p. 1502 - 1506 (2019/04/17)
Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. In particular, compound 23, the most potent NAMPT inhibitor (IC50 = 5.08 nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC50 values of 2.90 nM, 2.34 nM, and 2.24 nM, respectively, and even subnanomolar level against K562, MCF-7, and HUH7 cells with IC50 values of 0.46 nM, 0.23 nM and 0.53 nM, respectively. Our findings provided promising lead compounds for the discovery of more potent NAMPT inhibitors as anticancer drugs.
Aryl uracil compound or agriculturally acceptable salt and preparation method thereof and herbicide composition
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, (2019/02/03)
The invention provides an aryl uracil compound represented by a formula I (shown in the description) or agriculturally acceptable salt thereof. According to the formula I, R1 and R2 are independentlyselected from hydrogen, amino, C1-C4 alkyl or C1-C4 alkyl halide; X and Y are independently selected from hydrogen, halogen, nitryl, cyan, C1-C4 alkyl or substituted C1-C4 alkyl; R3 is selected from hydrogen, cyan or C1-C4 alkyl; and R4 is selected from cyan, nitryl, substituted or unsubstituted phenyl, substituted or unsubstituted five-membered or six-membered aromatic heterocyclic radical or a substituent group represented by a formula II (shown in the description), wherein R5 is selected from halogen, R6 and R7 are independently selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 alkyl halide. The compound has the characteristics of wide weed control spectrum and high herbicidal activity. The invention further provides a preparation method of the aryl uracil compound or the agriculturally acceptable salt of the aryl uracil compound and a herbicide composition.
Discovery of meta-sulfamoyl N-hydroxybenzamides as HDAC8 selective inhibitors
Zhao, Chunlong,Zang, Jie,Ding, Qin'ge,Inks, Elizabeth S.,Xu, Wenfang,Chou, C. James,Zhang, Yingjie
, p. 282 - 291 (2018/03/21)
In the past decade, although research and development of histone deacetylase (HDAC) inhibitors as therapeutic agents have achieved great accomplishments, especially in oncology field, there is still an urgent need for the discovery of isoform-selective HDAC inhibitors considering the side effects caused by nonselective HDAC inhibitors. HDAC8, a unique class I zinc-dependent HDAC, is becoming a potential target in cancer and other diseases. In the current study, a novel series of N-hydroxy-3-sulfamoylbenzamide-based HDAC8 selective inhibitors (12a-12p) were designed and synthesized, among which compounds 12a, 12b and 12c exhibited potent HDAC8 inhibition with two-digit nanomolar IC50 values, and considerable selectivity over HDAC2 (>180-fold) and HDAC6 (～30-fold) which was confirmed by western blot analysis. It is worth noting that 12a, 12b and 12c displayed highly selective anti-proliferative activity to T-cell leukemia cell lines Jurkat, Molt-4 and neuroblastoma cell line SK-N-BE-(2). Such selective cytotoxicity was also observed in the well-known HDAC8 selective inhibitor PCI-34051 but not in the pan-HDAC inhibitors SAHA and PXD101, indicating that HDAC8 selective inhibitor should have preferable benefit-risk profile in comparison with pan-HDAC inhibitor. Finally, the HDAC8 selectivity of 12a, 12b and 12c was rationalized by molecular docking study.
Histone deacetylase 8 selective inhibitor, as well as preparation method and application thereof
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, (2019/01/05)
The invention discloses a histone deacetylase 8 selective inhibitor, as well as a preparation method and application thereof. The histone deacetylase 8 selective inhibitor has a structure as shown ina general formula (I) or (II) below. The invention further provides a preparation method of the compound and application in preparing medicines for preventing or treating diseases relevant to histonedeacetylase 8 (HDAC8) activity abnormality.
Nitrogen-containing heterocycle derivatives and applications thereof
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, (2018/03/24)
The invention discloses nitrogen-containing heterocycle derivatives and applications thereof, relates to compounds of a general formula (V), a preparing method thereof and applications of the compounds in medicines, and more particularly relates to compound derivatives of compounds shown as the general formula (V), a preparing method thereof and uses of the derivatives in medicines preventing andtreating hyperlipemia, hypercholesterolemia, hypertriglyceridemia, fatty degeneration of liver, diabetes mellitus type 2, hyperglycemia, obesity or insulin resistance and metabolic syndrome and resisting antitumor, with the derivatives being adopted as therapeutic agents. The compounds disclosed by the invention can also reduce total cholesterol, LDL-cholesterol and triglyceride, can increase liver LDL receptor expression, and inhibit PCSK9 expression.
Aromatic Chlorosulfonylation by Photoredox Catalysis
Májek, Michal,Neumeier, Michael,Jacobi von Wangelin, Axel
, p. 151 - 155 (2017/01/17)
Visible-light photoredox catalysis enables the efficient synthesis of arenesulfonyl chlorides from anilines. The new protocol involves the convenient in situ preparation of arenediazonium salts (from anilines) and the reactive gases SO2and HCl (from aqueous SOCl2). The photocatalytic chlorosulfonylation operates at mild conditions (room temperature, acetonitrile/water) with low catalyst loading. Various functional groups are tolerated (e.g., halides, azides, nitro groups, CF3, SF5, esters, heteroarenes). Theoretical and experimental studies support a photoredox-catalysis mechanism.
Synthesis of biaryls via intramolecular free radical ipso-substitution reactions
Ujjainwalla, Feroze,Da Mata, Maria Lucília E.N.,Pennell, Andrew M.K.,Escolano, Carmen,Motherwell, William B.,Vázquez, Santiago
supporting information, p. 6701 - 6719 (2015/08/24)
A variety of functionalised biaryls and heterobiaryls are prepared by intramolecular free radical [1,5]-ipso-substitution using sulfonamide and sulfonate derived tethering chains. The overall efficiency of the process is determined by appropriately positioned substituents on the aromatic acceptor ring. The extension of the process to benzylic sulfonates and their corresponding N-methylsulfonamide alternatives as substrates in potential [1,6]-ipso-substitution reactions leads mainly to the alternative [1,7] addition products.
Development of first lead structures for phosphoinositide 3-kinase-c2γ inhibitors
Freitag, Anne,Prajwal, Prajwal,Shymanets, Aliaksei,Harteneck, Christian,Nürnberg, Bernd,Sch?chtele, Christoph,Kubbutat, Michael,Totzke, Frank,Laufer, Stefan A.
supporting information, p. 212 - 221 (2015/03/03)
The importance of complete elucidation of the biological functions of phosphoinositide 3-kinases (PI3K) was realized years ago. They generate 3-phosphoinositides, which are known to function as important second messengers in many inter- and intracellular signaling pathways. However, the functional role of class II PI3Ks is still unclear. Herein, we describe the synthesis of a panel of compounds that were tested against all eight mammalian PI3K-isoforms. We found inhibitors with some selectivity for class II PI3K-C2γ and also compounds with preferred inhibition of class II PI3K-C2β, providing structural leads to develop selective tool compounds.
