- 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones designed by a “cut and glue” strategy are dual aurora a/vegf-r kinase inhibitors
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Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines.
- Berger, Bianca,Chaikuad, Apirat,Karatas, Mehmet,Knapp, Stefan,Kubbutat, Michael H. G.,Kunick, Conrad,Totzke, Frank
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supporting information
(2021/06/16)
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- Discovery of New Imidazo[2,1- b]thiazole Derivatives as Potent Pan-RAF Inhibitors with Promising in Vitro and in Vivo Anti-melanoma Activity
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BRAF is an important component of MAPK cascade. Mutation of BRAF, in particular V600E, leads to hyperactivation of the MAPK pathway and uncontrolled cellular growth. Resistance to selective inhibitors of mutated BRAF is a major obstacle against treatment of many cancer types. In this work, a series of new (imidazo[2,1-b]thiazol-5-yl)pyrimidine derivatives possessing a terminal sulfonamide moiety were synthesized. Pan-RAF inhibitory effect of the new series was investigated, and structure-activity relationship is discussed. Antiproliferative activity of the target compounds was tested against the NCI-60 cell line panel. The most active compounds were further tested to obtain their IC50 values against cancer cells. Compound 27c with terminal open chain sulfonamide and 38a with a cyclic sulfamide moiety showed the highest activity in enzymatic and cellular assay, and both compounds were able to inhibit phosphorylation of MEK and ERK. Compound 38a was selected for testing its in vivo activity against melanoma. Cellular and animal activities are reported.
- Abdel-Maksoud, Mohammed S.,El-Gamal, Mohammed I.,Lee, Bong S.,Gamal El-Din, Mahmoud M.,Jeon, Hong R.,Kwon, Dow,Ammar, Usama M.,Mersal, Karim I.,Ali, Eslam M. H.,Lee, Kyung-Tae,Yoo, Kyung Ho,Han, Dong Keun,Lee, Jae Kyun,Kim, Garam,Choi, Hong Seok,Kwon, Young Jik,Lee, Kwan Hyi,Oh, Chang Hyun
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p. 6877 - 6901
(2021/06/25)
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- CHROMENOPYRIDINE DERIVATIVES AS PHOSPHATIDYLINOSITOL PHOSPHATE KINASE INHIBITORS
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The invention relates to inhibitors of PI5P4K inhibitors useful in the treatment of cancers, neurodegenerative diseases, inflammatory disorders, and metabolic diseases, having the Formula (I); where A1, A2, G, R1, R2, R3, R4, and W are described herein.
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Paragraph 0662
(2019/07/13)
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- AMINOPYRIDINE DERIVATIVES AS PHOSPHATIDYLINOSITOL PHOSPHATE KINASE INHIBITORS
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The invention relates to inhibitors of PI5P4K inhibitors useful in the treatment of cancers, neurodegenerative diseases, inflammatory disorders, and metabolic diseases, having the Formula: (I) where A, B, R1, X1, X2, and W are described herein.
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Paragraph 0770
(2019/07/13)
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- IMIDAZOOXAZOLE DERIVATIVE HAVING ANTITUMOR EFFECT, AND PHARMACEUTICAL COMPOSITION INCLUDING SAME
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Provided is a pharmaceutical composition for preventing and treating tumors, the pharmaceutical composition including an imidazooxazole derivative compound, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient.
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Paragraph 0053; 0054
(2019/05/22)
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- 6,7-DIHYDRO-4H-PYRAZOLO[1,5-A]PYRAZINE AND 6,7-DIHYDRO-4H-TRIAZOLO[1,5-A]PYRAZINE COMPOUNDS FOR THE TREATMENT OF INFECTIOUS DISEASES
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The present invention relates to compounds of the formula (I), or pharmaceutically acceptable salts, enantiomer or diastereomer thereof, wherein R1 to R4 and Q are as described above. The compounds may be useful for the treatment or prophylaxis of hepatitis B virus infection.
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Page/Page column 31
(2018/03/28)
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- Carbazole-containing sulfonamides and sulfamides: Discovery of cryptochrome modulators as antidiabetic agents
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A series of novel carbazole-containing sulfonamides and sulfamides were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the results of efficacy studies in diet-induced obese (DIO) mice, and the desired pharmacokinetic parameters, compound 41 was selected for further profiling.
- Humphries, Paul S.,Bersot, Ross,Kincaid, John,Mabery, Eric,McCluskie, Kerryn,Park, Timothy,Renner, Travis,Riegler, Erin,Steinfeld, Tod,Turtle, Eric D.,Wei, Zhi-Liang,Willis, Erik
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p. 757 - 760
(2016/05/24)
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- INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION
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Compounds of Formula I, including pharmaceutically acceptable salts thereof, and compositions and methods for treating human immunodeficiency virus (HIV) infection are set forth: (I)
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Page/Page column 83
(2016/11/14)
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- Carbazole-Containing Sulfonamides as Cryptochrome Modulators
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The subject matter herein is directed to carbazole-containing sulfonamide derivatives and pharmaceutically acceptable salts or hydrates thereof of structural formula I wherein the variable R1, R2, R3, R4, R5, R6, R7, A, B, C, D, E, F, G, H, a, and b are accordingly described. Also provided are pharmaceutical compositions comprising the compounds of formula I to treat a Cry-mediated disease or disorder, such as diabetes, obesity, metabolic syndrome, Cushing's syndrome, and glaucoma.
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Paragraph 0433-0434
(2013/11/19)
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- Synthesis of new 6-(4-Fluorophenyl)-5-(2-substituted pyrimidin-4-yl) imidazo[2,1-b] thiazole derivatives and their antiproliferative activity against melanoma cell line
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Synthesis of a new series of pyrimidinyl-imidazo[2,1-b]thiazole derivatives is described. Their antiproliferative activity against A375 human melanoma cell line was tested and the effect of substituents on the pyrimidinyl ring side chain was investigated.
- Park, Jin-Hun,Oh, Chang-Hyun
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experimental part
p. 2854 - 2860
(2012/04/17)
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- ASPARTYL PROTEASE INHIBITORS
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A compound of formula (I): N-oxides, addition salts, quaternary amines metal complexes stereochemically isomeric forms and metabolites thereof, wherein A is CR1 or N; D is H, C1-C6alkyl, C2-C6alkenyl,
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Page/Page column 70
(2010/04/28)
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- Novel lβ-methylcarbapenems having cyclic sulfonamide moieties: Synthesis and evaluation of in-vitro biological activity - Part II
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The synthesis of a new series of 1β-methylcarbapenems having cyclic sulfonamide moieties is described. Their in-vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of a substituent on the pyrroli
- Seong, Jong Kim,Cho, Jung-Hyuck,Oh, Chang-Hyun
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scheme or table
p. 528 - 532
(2009/12/06)
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- Synthesis and antibacterial activities of novel oxazolidinones having cyclic sulfonamide moieties
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The synthesis of a new series of oxazolidinones having cyclic sulfonamide moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the oxazolidinone
- Kim, Seoung Jong,Jung, Myung-Ho,Yoo, Kyung Ho,Cho, Jung-Hyuck,Oh, Chang-Hyun
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scheme or table
p. 5815 - 5818
(2009/11/30)
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- Novel lβ-methylcarbapenems having cyclic sulfonamide moieties: Synthesis and evaluation of in vitro antibacterial activity
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The synthesis of a new series of 1β-methylcarbapenems having cyclic sulfonamide moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituent on the pyrrolidi
- Kim, Seong Jong,Park, Hyeong Beom,Lee, Jae Seoung,Jo, Nam Hyun,Yoo, Kyung Ho,Baek, Daejin,Kang, Byoung-won,Cho, Jung-Hyuck,Oh, Chang-Hyun
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p. 1176 - 1183
(2008/03/17)
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- New uses for the Burgess reagent in chemical synthesis: Methods for the facile and stereoselective formation of sulfamidates, glycosylamines, and sulfamides
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Although the Burgess reagent (methoxycarbonylsulfamoyltriethylammonium hydroxide, inner salt) has found significant use in chemical synthesis as a dehydrating agent, almost no work has been directed towards its potential in other synthetic applications. As this article will detail, we have found that the Burgess reagent is remarkably effective at accomplishing a number of non-dehydrative synthetic tasks when applied to appropriate substrates, such as the formation of sulfamidates from 1,2-diols or epoxyalcohols, α- and β-glycosylamines from carbohydrates, and cyclic sulfamides from 1,2-aminoalcohols. Beyond delineating the power of these new reaction manifolds, we also describe the construction of a group of alternative Burgess-type reagents that extends the scope of these new reactions even further.
- Nicolaou,Snyder, Scott A.,Longbottom, Deborah A.,Nalbandian, Annie Z.,Huang, Xianhai
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p. 5581 - 5606
(2007/10/03)
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- Synthesis of non-symmetrical sulfamides using burgess-type reagents
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A practical and high-yielding method for the efficient, one-step synthesis of diverse classes of N,N′-differentiated sulfamides employs a wide range of amino alcohols and simple amines using Burgess-type reagents. This methodology extends the application
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- A new method for the synthesis of nonsymmetrical sulfamides using Burgess-type reagents
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A practical and high-yielding method for the efficient, one-step synthesis of diverse classes of N,N′-differentiated sulfamides has been developed from a wide range of amino alcohols and simple amines using Burgess-type reagents (see scheme). This method
- Nicolaou,Longbottom, Deborah A.,Snyder, Scott A.,Nalbanadian, Annie Z.,Huang, Xianhai
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p. 3866 - 3870
(2007/10/03)
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- Synthesis and Biological Activity of 3--5--1H-indole and Analogues: Agonists for the 5-HT1D Receptor
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A novel series of 5-(1,1-dioxo-1,2,5-thiadiazolidin-2-yl)tryptamines was designed, synthesized, and evaluated as 5-HT1D receptor agonists.Compounds such as 8d,f,k were identified which had comparable affinity, potency, and receptor selectivity
- Castro, Jose L.,Baker, Raymond,Guiblin, Alexander R.,Hobbs, Sarah C.,Jenkins, Matthew,et al.
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p. 3023 - 3032
(2007/10/02)
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- Nitroimidazoles: Part V - 1-(1-Methyl-5-nitroimidazol-2-yl)-1,2,4-triazolidin-3,5-diones and Analogues
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Condensation of 1-methyl-2-methylsulphonyl-5-nitroimidazole (1) with the sodium salts of triazolindiones affords the derivatives 2a-i; similiar reaction with the sodium salts of thiazolidinone, 2-iminothiazolidine, pyrrolidinone, oxazolidinone and its 2-methyl and 2-chloromethyl analogues leads to the formation of products 3-8 respectively.Under the reaction conditions 3 is opened by dimethylamide ion to form 10, and 6 by methyl sulfinate ion to provide 13 respectively.Additionally, 6 is hydrolysed to the amine (12).Cyclic sulphamides undergo reaction with 1 to provide nitroimidazoles (23-28).
- Arya, V. P.,Nagarajan, K.,Shenoy, S. J.
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p. 941 - 944
(2007/10/02)
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