- Design, synthesis, and biological activity evaluation of a series of novel sulfonamide derivatives as BRD4 inhibitors against acute myeloid leukemia
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Accumulating researches have contributed much effect to discover novel chemotherapeutic drug for leukemia with expeditious curative effect, of which bromodomain-containing protein 4 (BRD4) inhibitor is considered as a eutherapeutic drug which has presented efficient cell proliferation suppression effect. In this study, we disclosed a series of phenylisoxazole sulfonamide derivatives as potent BRD4 inhibitors. Especially, compound 58 exhibited robust inhibitory potency toward BRD4-BD1 and BRD4-BD2 with IC50 values of 70 and 140 nM, respectively. In addition, compound 58 significantly suppressed cell proliferation of leukemia cell lines HL-60 and MV4-11 with IC50 values of 1.21 and 0.15 μM. In-depth study of the biological mechanism of compound 58 exerted its tumor suppression effect via down-regulating the level of oncogene c-myc. Moreover, in vivo pharmacokinetics (PK) study was conducted and the results demonstrated better pharmacokinetics features versus (+)-JQ1. In summary, our study discovers that compound 58 represents as a novel BRD4 inhibitor for further investigation in development of leukemia inhibitor with potentiality.
- Chen, Aiping,Feng, Ziying,Huang, Wenlong,Li, Jieming,Liu, Xinhong,Qian, Hai,Qiu, Qianqian,Shi, Jing,Shi, Wei,Zhang, Wenjie,Zhou, Daoguang
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supporting information
(2021/07/22)
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- Metal-Free Twofold Electrochemical C?H Amination of Activated Arenes: Application to Medicinally Relevant Precursor Synthesis
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The efficient production of many medicinally or synthetically important starting materials suffers from wasteful or toxic precursors for the synthesis. In particular, the aromatic non-protected primary amine function represents a versatile synthetic precu
- D?rr, Carolin,Diehl, Erika,Hellmich, Ute A.,Schollmeyer, Dieter,Shimizu, Akihiro,Waldvogel, Siegfried R.,Wesenberg, Lars J.,Yoshida, Jun-ichi,Z?hringer, Till J. B.
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supporting information
p. 17574 - 17580
(2020/12/07)
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- Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent and orally bioavailable tissue-nonspecific alkaline phosphatase (TNAP) inhibitor
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Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme crucial for bone matrix mineralization via its ability to hydrolyze extracellular inorganic pyrophosphate (ePPi), a potent mineralization inhibitor, to phosphate (Pi). B
- Pinkerton, Anthony B.,Sergienko, Eduard,Bravo, Yalda,Dahl, Russell,Ma, Chen-Ting,Sun, Qing,Jackson, Michael R.,Cosford, Nicholas D.P.,Millán, José Luis
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- Design of Benzoxathiazin-3-one 1,1-Dioxides as a New Class of Irreversible Serine Hydrolase Inhibitors: Discovery of a Uniquely Selective PNPLA4 Inhibitor
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The design and examination of 4,1,2-benzoxathiazin-3-one 1,1-dioxides as candidate serine hydrolase inhibitors are disclosed, and represent the synthesis and study of a previously unexplored heterocycle. This new class of activated cyclic carbamates provi
- Kornahrens, Anne F.,Cognetta, Armand B.,Brody, Daniel M.,Matthews, Megan L.,Cravatt, Benjamin F.,Boger, Dale L.
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p. 7052 - 7061
(2017/05/31)
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- 1,3,5-TRIAZINE-2-AMINE DERIVATIVES, PREPARATION THEREOF AND DIAGNOSTIC AND THERAPEUTIC USE THEREOF
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The present invention relates to compounds corresponding to formula (I) in which: - R1 represents a substituted phenyl; - R2 represents: - a substituted phenyl; - a heteroaromatic group, the said group being unsubstituted or substituted one or more times; - R3 represents a group Alk; - R4 represents a hydrogen atom or a (C1-C4)alkyl; - R5 represents a hydrogen atom, a (C3-C6)cycloalkyl or a (C1-C4)alkyl-O-Alk; - or alternatively R4 and R5, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, morpholin-4-yl; - R6 represents a group -COOAlk, a group -CONH2 or a group -NHSO2 Alk; - Alk represents a (C1-C4)alkyl, which is unsubstituted or substituted one or more times with a halogen atom; in the form of the base or of an acid-addition salt. Preparation process and diagnostic and therapeutic use
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Page/Page column 14-15
(2013/07/05)
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- SULFONAMIDE COMPOUNDS AND USES AS TNAP INHIBITORS
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Described herein are compounds that modulate the activity of TNAP. In some embodiments, the compounds described herein inhibit TNAP. In certain embodiments, the compounds described herein are useful in the treatment of conditions associated with hyper- mineralization.
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Paragraph 00494-00495
(2013/09/12)
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- Discovery of a novel series of potent and orally bioavailable phosphoinositide 3-kinase γ inhibitors
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The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kγ revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.
- Leahy, James W.,Buhr, Chris A.,Johnson, Henry W. B.,Kim, Byung Gyu,Baik, Taegon,Cannoy, Jonah,Forsyth, Timothy P.,Jeong, Joon Won,Lee, Matthew S.,Ma, Sunghoon,Noson, Kevin,Wang, Longcheng,Williams, Matthew,Nuss, John M.,Brooks, Eric,Foster, Paul,Goon, Leanne,Heald, Nathan,Holst, Charles,Jaeger, Christopher,Lam, Scott,Lougheed, Julie,Nguyen, Lam,Plonowski, Arthur,Song, Joanne,Stout, Thomas,Wu, Xiang,Yakes, Michael F.,Yu, Peiwen,Zhang, Wentao,Lamb, Peter,Raeber, Olivia
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experimental part
p. 5467 - 5482
(2012/09/25)
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- Dihydrobenzoxathiazepine compounds, a process for their preparation and pharmaceutical compositions containing them
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Compounds of formula (I): wherein R1 represents a hydrogen atom or a heterocyclic, cyano, alkoxycarbonyl, alkylsulphonylaminoalkyl or N-hydroxycarboximidamide group. Medicinal products containing the same which are useful as modulators of the A
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Page/Page column 5
(2012/04/04)
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