158985-36-5Relevant articles and documents
ROR [gamma]t inhibitor, preparation method and application thereof
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Paragraph 1342; 1344-1346, (2021/07/08)
The invention relates to the technical field of medicines, in particular to an ROR [gamma]t inhibitor, a preparation method and application thereof. The invention also relates to a pharmaceutical composition containing the compound, a method for preparing the pharmaceutical composition, and application of the compound or the pharmaceutical composition in treatment or prevention of ROR [gamma]t-mediated cancers, inflammations or autoimmune diseases of mammals, especially human beings.
Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations
Cai, Jiongheng,Chen, Yadong,Chen, Yun,Cheng, Jie,Cheng, Zitian,Heng, Hao,Huang, Fei,Jia, Kun,Li, Hongmei,Lu, Shuai,Lu, Tao,Ren, Jiwei,Sheng, Tiancheng,Song, Shiyu,Tang, Weifang,Wang, Zhijie,Wu, Yingli,Zhu, Yifan
, p. 14664 - 14701 (2021/10/12)
Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitor resistance that presents a significant clinical challenge. Herein, a series of pyrazole-3-amine derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. The structure-activity relationship and molecular dynamics simulation studies illustrated that the ribose region of FLT3 could be occupied to help address the obstacle of secondary mutations. Among those derivatives, compound 67 exhibited potent and selective inhibitory activities against FLT3-ITD-positive acute myeloid leukemia (AML) cells and possessed equivalent potency against transformed BaF3 cells with a variety of secondary mutations. Besides, cellular mechanism assays demonstrated that 67 strongly inhibited phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and apoptosis in MV4-11 cells. In the MV4-11 xenograft models, 67 exhibited potent antitumor potency without obvious toxicity. Taken together, these results demonstrated that 67 might be a drug candidate for the treatment of FLT3-ITD-positive AML.
PYRAZOLOTRIAZOLOPYRIMIDINE DERIVATIVES AS A2A RECEPTOR ANTAGONIST
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Paragraph 0653-0655, (2020/02/16)
Disclosed herein is a pyrazolotriazolopyrimidine derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof useful as A2A receptor antagonist, and a pharmaceutical composition comprising the same. Also disclosed herein is a method of treating cancer using the pyrazolotriazolopyrimidine derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as A2A receptor antagonist.
Combining structure- and property-based optimization to identify selective FLT3-ITD inhibitors with good antitumor efficacy in AML cell inoculated mouse xenograft model
Heng, Hao,Wang, Zhijie,Li, Hongmei,Huang, Yatian,Lan, Qingyuan,Guo, Xiaoxing,Zhang, Liang,Zhi, Yanle,Cai, Jiongheng,Qin, Tianren,Xiang, Li,Wang, Shuxian,Chen, Yadong,Lu, Tao,Lu, Shuai
, p. 248 - 267 (2019/05/21)
FLT3 mutation is among the most common genetic mutations in acute myeloid leukemia (AML), which is also related with poor overall survival and refractory in AML patients. Recently, FLT3 inhibitors have been approved for AML therapy. Herein, a series of new compounds with pyrazole amine scaffold was discovered, which showed potent inhibitory activity against FLT3-ITD and significant selectivity against both FLT3-ITD and AML cells expressing FLT3-ITD. Compound 46, possessing the most promising cellular activity, blocked the autophosphorylation of FLT3 pathway in MV4-11 cell line. Furthermore, the apoptosis and downregulation of P-STAT5 were also observed in tumor cells extracted from the MV4-11 cell xenografts model upon compound 46 treatment. Compound 46 was also metabolically stable in vitro and suppressed tumor growth significantly in MV4-11 xenografts model in vivo. Compound 46 showed no toxicity to the viscera of mice and caused no decrease in body weight of mice. In conclusion, the results of this study could provide valuable insights into discovery of new FLT3 inhibitors, and compound 46 was worthy of further development as potential drug candidate to treat AML.
CEREBLON LIGANDS AND BIFUNCTIONAL COMPOUNDS COMPRISING THE SAME
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Paragraph 1010; 1011; 1012, (2018/08/20)
The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
SELECTIVE HDAC1,2 INHIBITORS
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Paragraph 0257; 0258; 0259; 0282; 0283, (2018/06/04)
Provided herein are compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat diseases or disorders associated with HDAC1 and/or HDAC2 activity.
Metal-free Synthesis of Aryl Amines: Beyond Nucleophilic Aromatic Substitution
Sandtorv, Alexander H.,Stuart, David R.
, p. 15812 - 15815 (2016/12/16)
A mild and metal-free approach to C?N coupling is described that employs diaryliodonium salt electrophiles and secondary aliphatic amine nucleophiles. This reaction results in direct ipso-substitution of the iodonium moiety and unsymmetrical aryl(TMP)iodonium salts are primarily employed. Moreover, arene substituents and substitution patterns that currently pose a challenge to classical metal-free methods are accommodated and the alicyclic amine nucleophiles used here are unprecedented in other contemporary metal-free C?N coupling reactions.
Mechanisms of action of novel influenza A/M2 viroporin inhibitors derived from hexamethylene amiloride
Jalily, Pouria H.,Eldstrom, Jodene,Miller, Scott C.,Kwan, Daniel C.,Tai, Sheldon S.-H.,Chou, Doug,Niikura, Masahiro,Tietjen, Ian,Fedida, David
supporting information, p. 80 - 95 (2016/07/28)
The increasing prevalence of influenza viruses with resistance to approved antivirals highlights the need for new anti-influenza therapeutics. Here we describe the functional properties of hexamethylene amiloride (HMA)'derived compounds that inhibit the wildtype and adamantane-resistant forms of the influenza A M2 ion channel. For example, 6-(azepan-1-yl)-N-carbamimidoylnicotinamide (9) inhibits amantadine-sensitive M2 currents with 3- to 6-fold greater potency than amantadine or HMA (IC50 5 0.2 vs. 0.6 and 1.3 μM, respectively). Compound 9 competes with amantadine for M2 inhibition, and molecular docking simulations suggest that 9 binds at site(s) that overlap with amantadine binding. In addition, tert-butyl 4′-(carbamimidoylcarbamoyl)-2′,3-dinitro- [1,1′-biphenyl]-4-carboxylate (27) acts both on adamantanesensitive and a resistantM2variant encoding a serine to asparagine 31 mutation (S31N) with improved efficacy over amantadine and HMA (IC5050.6 μMand4.4mM, respectively).Whereas 9 inhibited in vitro replication of influenza virus encoding wild-type M2 (EC505 2.3 μM), both 27 and tert-butyl 4′-(carbamimidoylcarbamoyl)-2′,3- dinitro-[1,1′-biphenyl]-4-carboxylate (26) preferentially inhibited viruses encoding M2(S31N) (respective EC50 5 18.0 and 1.5 μM). This finding indicates thatHMAderivatives can be designed to inhibit viruses with resistance to amantadine. Our study highlights the potential of HMA derivatives as inhibitors of drug-resistant influenza M2 ion channels.
Synthesis, biological evaluation, X-ray molecular structure and molecular docking studies of RGD mimetics containing 6-amino-2,3-dihydroisoindolin-1-one fragment as ligands of integrin αiIbβ3
Krysko, Andrei A.,Samoylenko, Georgiy V.,Polishchuk, Pavel G.,Fonari, Marina S.,Kravtsov, Victor Ch.,Andronati, Sergei A.,Kabanova, Tatyana A.,Lipkowski, Janusz,Khristova, Tetiana M.,Kuz'Min, Victor E.,Kabanov, Vladimir M.,Krysko, Olga L.,Varnek, Alexandre A.
, p. 4646 - 4661 (2013/07/26)
A series of novel RGD mimetics containing phthalimidine fragment was designed and synthesized. Their antiaggregative activity determined by Born's method was shown to be due to inhibition of fibrinogen binding to αIIbβ3. Molecular docking of RGD mimetics to αIIbβ3 receptor showed the key interactions in this complex, and also some correlations have been observed between values of biological activity and docking scores. The single crystal X-ray data were obtained for five mimetics.
Synthesis and SAR of piperazinyl-N-phenylbenzamides as inhibitors of hepatitis C virus RNA replication in cell culture
Conte, Immacolata,Giuliano, Claudio,Ercolani, Caterina,Narjes, Frank,Koch, Uwe,Rowley, Michael,Altamura, Sergio,Francesco, Raffaele De,Neddermann, Petra,Migliaccio, Giovanni,Stansfield, Ian
scheme or table, p. 1779 - 1783 (2009/12/03)
The RNA replication machinery of HCV is a multi-subunit membrane-associated complex. NS5A has emerged as an active component of HCV replicase, possibly involved in regulation of viral replication and resistance to the antiviral effect of interferon. We report here substituted piperazinyl-N-(aryl)benzamides as potent inhibitors of HCV replication exerted via modulation of the dimerization of NS5A.
