- Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity
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IRAK4 kinase activity transduces signaling from multiple IL-1Rs and TLRs to regulate cytokines and chemokines implicated in inflammatory diseases. As such, there is high interest in identifying selective IRAK4 inhibitors for the treatment of these disorders. We previously reported the discovery of potent and selective dihydrobenzofuran inhibitors of IRAK4. Subsequent studies, however, showed inconsistent inhibition in disease-relevant pharmacodynamic models. Herein, we describe application of a human whole blood assay to the discovery of a series of benzolactam IRAK4 inhibitors. We identified potent molecule 19 that achieves robust in vivo inhibition of cytokines relevant to human disease.
- Rajapaksa, Naomi S.,Gobbi, Alberto,Drobnick, Joy,Do, Steven,Kolesnikov, Aleksandr,Liang, Jun,Chen, Yongsheng,Sujatha-Bhaskar, Swathi,Huang, Zhiyu,Brightbill, Hans,Francis, Ross,Yu, Christine,Choo, Edna F.,Dement, Kevin,Ran, Yingqing,An, Le,Emson, Claire,Maher, Jonathan,Wai, John,McKenzie, Brent S.,Lupardus, Patrick J.,Zarrin, Ali A.,Kiefer, James R.,Bryan, Marian C.
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supporting information
p. 327 - 333
(2019/12/02)
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- PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
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Compounds of Formula (0), Formula (I), and Formula (II) and methods of use as Interleukin-1 Receptor Associated Kinase (IRAK4) inhibitors are described herein.
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Page/Page column 620
(2017/07/14)
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- A method for preparing the methyl two sulphur are prosperous (by machine translation)
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The invention discloses a method for synthesizing the methyl two sulphur are prosperous, belongs to the pesticide chemical field, the synthetic method is to 4 - chloro - 2 - aminobenzoic acid as the raw materials, by esterification, diazo, through sulfur dioxide, oxychloride, ammoniation ring, nitrogen methylation, carbonitriding, reduction, open-loop, a sulfonylation and condensation of the eleven step to make the methyl two sulphur are prosperous. The invention synthetic the methyl two sulphur are prosperous, the raw material is cheap, simple operation, mild condition, low equipment requirements, high yield, is suitable for industrial production, and the practicability is strong. (by machine translation)
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- DERIVATIVES OF BENZOTHIAZINES, PREPARATION THEREOF AND APPLICATION THEREOF AS DRUGS
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The object of the present invention is benzothiazine derivatives having the capability of inhibiting 11β-HSD1 not only at an enzymatic level but also at a cell level. The compounds of the present invention are of general formula (I). Wherein notably R1 represents a hydrogen or OR1 represents an ester or an ether. R2 represents a naphthyl or a 1, 2, 3, 4-tetrahydro-naphthalene or a biphenyl or phenyl pyridine or a substituted phenyl. R3 represents a methyl or ethyl; R4 and R'4 represent a hydrogen.
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Page/Page column 107
(2010/09/18)
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- Oxidative cyclization of N-alkyl-o-methyl-arenesulfonamides to biologically important saccharin derivatives
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Various biologically important saccharin skeletons and their N-alkyl derivatives have been efficiently prepared by chromium(VI) oxide catalyzed H5IO6 oxidation of N-alkyl-o-methyl-arenesulfonamides in acetonitrile. N-tert-Butyl saccharin skeletons were easily prepared by H5IO6-CrO3 oxidation of N-tert-butyl-o-methyl arenesulfonamides in the presence of acetic anhydride. The method that furnished the novel fluoro and trifluoromethyl substituted saccharin skeletons is characterized by two steps, a simple work-up procedure, a single purification and good overall yields from substituted toluene derivatives.
- Xu, Liang,Shu, Hong,Liu, Ying,Zhang, Suhong,Trudell, Mark L.
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p. 7902 - 7910
(2007/10/03)
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- Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: Synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives
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In a previous study, we described the structure-activity relationships (SARs) for a series of thiazolidenebenzenesulfonamide derivatives. These compounds were found to be highly potent inhibitors of the wild type (WT) and Y181C mutant reverse transcriptas
- Masuda, Naoyuki,Yamamoto, Osamu,Fujii, Masahiro,Ohgami, Tetsuro,Fujiyasu, Jiro,Kontani, Toru,Moritomo, Ayako,Orita, Masaya,Kurihara, Hiroyuki,Koga, Hironobu,Kageyama, Shunji,Ohta, Mitsuaki,Inoue, Hiroshi,Hatta, Toshifumi,Shintani, Masafumi,Suzuki, Hiroshi,Sudo, Kenji,Shimizu, Yasuaki,Kodama, Eiichi,Matsuoka, Masao,Fujiwara, Masatoshi,Yokota, Tomoyuki,Shigeta, Shiro,Baba, Masanori
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p. 949 - 961
(2007/10/03)
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- Facile synthesis of 1, 2-benzisothiazole-3-one-1,1-dioxide methylsulfonyl derivatives
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An improved and general synthesis of saccharin methylthio and methylsulfone derivatives from chloro-substituted saccharins is presented. A large-scale procedure for preparation of chloro-substituted saccharins was developed. Treatment of the saccharin chlorides with sodium thiomethoxide and t-BuOK in DMF gave the saccharin methyl sulfides, which upon chromium(VI) oxide catalyzed oxidation with periodic acid afforded the corresponding saccharin methylsulfones in high yields.
- Xu, Liang,Trudell, Mark L.
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p. 435 - 438
(2007/10/03)
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- Some new 1,2-benzothiazine derivatives with analgesic and anti-inflammatory activities
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Twenty-three new 7-halo-4-hydroxy-2H(or alkyl)-N-(3-aralkyl-2-thio-l-hydantoinyl)-2H- 1,2-benzothiazine-3-carboxamide 1,1-dioxide derivatives were synthesized through the condensation of 7-halo-4-hydroxy-2H(or alkyl)-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxides with 1-amino-2-thio-3-aralkyl-imidazolidine-4-one. The analgesic and anti-inflammatory activities of the synthesized compounds were investigated by acetic acid-induced writhing syndrome and carrageenan rat paw edema tests. In analgesic activities most compounds exhibited higher activities than acetylsalicylic acid, but in antiinflammatory activities most compounds except compounds 24, 36, 39 showed lower activities than indometacin.
- Kwon, Soon-Kyoung,Park, Myung-Sook
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p. 966 - 971
(2007/10/03)
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- Herbicidal sulfonamides
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4-Chloro-2-[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]aminosulfonyl]benzoic acid (1-methylethyl) ester has unexpectedly been discovered to be an outstanding agricultural chemical. The compound is a highly active preemergent and/or postemergent herbicide. The invention includes the compound, compositions containing the compound, and its method-of-use as an agricultural chemical.
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