14389-86-7Relevant academic research and scientific papers
Structure-based design of cathepsin K inhibitors containing a benzyloxy- substituted benzoyl peptidomimetic
Thompson, Scott K.,Smith, Ward W.,Zhao, Baoguang,Halbert, Stacie M.,Tomaszek, Thaddeus A.,Tew, David G.,Levy, Mark A.,Janson, Cheryl A.,D'Alessio, Karla J.,McQueney, Michael S.,Kurdyla, Jeff,Jones, Christopher S.,Desjarlais, Renee L.,Abdel-Meguid, Sherin S.,Veber, Daniel F.
, p. 3923 - 3927 (1998)
Peptidomimetic cathepsin K inhibitors have been designed using binding models which were based on the X-ray crystal structure of an amino acid- based, active site-spanning inhibitor complexed with cathepsin K. These inhibitors, which contain a benzyloxybenzoyl group in place of a Cbz-leucine moiety, maintained good inhibitory potency relative to the amino acid-based inhibitor, and the binding models were found to be very predictive of relative inhibitor potency. The binding mode of one of the inhibitors was confirmed by X-ray crystallography, and the crystallographically determined structure is in close qualitative agreement with the initial binding model. These results strengthen the validity of a strategy involving iterative cycles of structure-based design, inhibitor synthesis and evaluation, and crystallographic structure determination for the discovery of peptidomimetic inhibitors.
Synthesis and evaluation of new sesamol-based phenolic acid derivatives with hypolipidemic, antioxidant, and hepatoprotective effects
Xie, Yundong,Liu, Jiping,Shi, Yongheng,Bin Wang,Wang, Xiaoping,Wang, Wei,Sun, Meng,Xu, Xinya,He, Shipeng
, p. 1688 - 1702 (2021/07/26)
The objective of this study is to synthesize a series of sesamol-based phenolic acid derivatives, which were designed by combination principle. The hypolipidemic activity of all these compounds was preliminarily screened by acute hyperlipidemic mice model induced by Triton WR 1339, in which compound T6 exhibited more significant reducing plasma TG and TC than fenofibrate. Compound T6 was also found to obviously decrease TG and TC both in the plasma and hepatic tissue of high-fat-diet-induced hyperlipidemic mice. Moreover, T6 showed hepatoprotective effects, which remarkable amelioration in characteristic liver enzymes was examined and the histopathological observation displayed that compound T6 inhibited lipids accumulation in the hepatic. The levels of PPAR-α receptor related to lipids metabolism in hepatic tissue were upregulated after T6 treatment. Other potent effects of T6 such as antioxidant and anti-inflammatory activity were also observed. On the bases of these findings, compound T6 may serve as an effective hypolipidemic and hepatoprotective agent. [Figure not available: see fulltext.]
Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors
Aylott, Helen E.,Atkinson, Stephen J.,Bamborough, Paul,Bassil, Anna,Chung, Chun-Wa,Gordon, Laurie,Grandi, Paola,Gray, James R. J.,Harrison, Lee A.,Hayhow, Thomas G.,Messenger, Cassie,Mitchell, Darren,Phillipou, Alexander,Preston, Alex,Prinjha, Rab K.,Rianjongdee, Francesco,Rioja, Inmaculada,Seal, Jonathan T.,Wall, Ian D.,Watson, Robert J.,Woolven, James M.,Demont, Emmanuel H.
, p. 3249 - 3281 (2021/04/06)
A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).
Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease
Bai, Renren,Gu, Jinping,Guo, Jianan,Jiang, Xiaoying,Xie, Yuanyuan,Zhang, Changjun,Zhou, Tao
, p. 2045 - 2054 (2021/10/08)
A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through pharmacophores-merged approaches based on lead compounds 18d, benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe3+ values ranging from 18.13 to 19.39. Among all the compounds, 8g exhibited the most potent selective MAO-B inhibitor (IC50 = 68.4 nM, SI = 213). Moreover, 8g showed favourable pharmacokinetic properties and had great potential to penetrate the BBB in silico and PAMPA-BBB assay. Molecular modelling showed that 8g could adopt an extended conformation and have more enhanced interactions with MAO-B than 18d. In vitro and in vivo assays demonstrated that 8g remarkably resisted Aβ-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound 8g is a potential multifunctional candidate for anti-AD treatment.
Polyhydrazide-Based Organic Nanotubes as Efficient and Selective Artificial Iodide Channels
Aksimentiev, Aleksei,Chen, Feng,Joshi, Himanshu,Roy, Arundhati,Shen, Jie,Ye, Ruijuan,Zeng, Huaqiang
supporting information, p. 4806 - 4813 (2020/02/11)
Reported herein is a series of pore-containing polymeric nanotubes based on a hydrogen-bonded hydrazide backbone. Nanotubes of suitable lengths, possessing a hollow cavity of about a 6.5 ? diameter, mediate highly efficient transport of diverse types of anions, rather than cations, across lipid membranes. The reported polymer channel, having an average molecular weight of 18.2 kDa and 3.6 nm in helical height, exhibits the highest anion-transport activities for iodide (EC50=0.042 μm or 0.028 mol % relative to lipid), whcih is transported 10 times more efficiently than chlorides (EC50=0.47 μm). Notably, even in cholesterol-rich environment, iodide transport activity remains high with an EC50 of 0.37 μm. Molecular dynamics simulation studies confirm that the channel is highly selective for anions and that such anion selectivity arises from a positive electrostatic potential of the central lumen rendered by the interior-pointing methyl groups.
Formamide pyridone iron chelating agent derivative with potential multi-target anti-AD activity as well as preparation method and application thereof
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Paragraph 0096-0097; 0100; 0240-0241; 0244, (2020/12/10)
The invention provides a formamide pyridone iron chelating agent derivative shown as a formula (I) or a formula (II) which is described in the specification and a preparation method and application thereof. The formamide pyridone iron chelating agent derivative shown in the formula (I) or the formula (II) and the pharmaceutically acceptable salt thereof have the effects of inhibiting monoamine oxidase, chelating metal iron ions, resisting A beta and resisting oxidation activity. The derivative can be used for preparing medicines for resisting Alzheimer's disease, Parkinson's disease or other diseases treated by inhibiting monoamine oxidase, chelating metal iron ions, resisting A beta and resisting oxidation.
How Many O-Donor Groups in Enterobactin Does It Take to Bind a Metal Cation?
Baramov, Todor,Schmid, Bianca,Ryu, Ho,Jeong, Jinhoon,Keijzer, Karlijn,von Eckardstein, Leonard,Baik, Mu-Hyun,Süssmuth, Roderich D.
supporting information, p. 6955 - 6962 (2019/04/17)
The E. coli siderophore enterobactin, the strongest FeIII chelator known to date, forms hexacoordinate complexes with SiIV, GeIV, and TiIV. Synthetic protocols have been developed to prepare non-symmetric entero
Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor
Li, Yali,Huang, Taomin,Lou, Bin,Ye, Deyong,Qi, Xiangyu,Li, Xiaoxia,Hu, Shuang,Ding, Tingbo,Chen, Yan,Cao, Yang,Mo, Mingguang,Dong, Jibin,Wei, Min,Chu, Yong,Li, Huiti,Jiang, Xian-Cheng,Cheng, Nengneng,Zhou, Lu
supporting information, p. 864 - 882 (2019/01/04)
The sphingomyelin synthase 2 (SMS2) is a potential target for pharmacological intervention in atherosclerosis. However, so far, few selective SMS2 inhibitors and their pharmacological activities were reported. In this study, a class of 2-benzyloxybenzamides were discovered as novel SMS2 inhibitors through scaffold hopping and structural optimization. Among them, Ly93 as one of the most potent inhibitors exhibited IC50 values of 91 nM and 133.9 μM against purified SMS2 and SMS1 respectively. The selectivity ratio of Ly93 was more than 1400-fold for purified SMS2 over SMS1. The in vitro studies indicated that Ly93 not only dose-dependently diminished apoB secretion from Huh7 cells, but also significantly reduced the SMS activity and increased cholesterol efflux from macrophages. Meanwhile, Ly93 inhibited the secretion of LPS-mediated pro-inflammatory cytokine and chemokine in macrophages. The pharmacokinetic profiles of Ly93 performed on C57BL/6J mice demonstrated that Ly93 was orally efficacious. As a potent selective SMS2 inhibitor, Ly93 significantly decreased the plasma SM levels of C57BL/6J mice. Furthermore, Ly93 was capable of dose-dependently attenuating the atherosclerotic lesions in the root and the entire aorta as well as macrophage content in lesions, in apolipoprotein E gene knockout mice treated with Ly93. In conclusion, we discovered a novel selective SMS2 inhibitor Ly93 and demonstrated its anti-atherosclerotic activities in vivo. The preliminary molecular mechanism-of-action studies revealed its function in lipid homeostasis and inflammation process, which indicated that the selective inhibition of SMS2 would be a promising treatment for atherosclerosis.
Metal-free Synthesis of Spiro-2,2′-benzo[b]furan-3,3′-ones via PhI(OAc)2-Mediated Cascade Spirocyclization
Xing, Qingyu,Liang, Huiyuan,Bao, Mingmai,Li, Xuemin,Zhang, Jingran,Bi, Tianhao,Zhang, Yilin,Xu, Jun,Du, Yunfei,Zhao, Kang
supporting information, p. 4669 - 4673 (2019/09/17)
Treating the benzyl protected 3-hydroxy-1,3-bis(2-hydroxyphenyl)prop-2-en-1-ones solely with PhI(OAc)2 (PIDA) in DCE at room temperature readily furnished the seldom studied spiro-2,2′-benzo[b]furan-3,3′-ones in satisfactory to excellent yields. The hypervalent iodine reagent enables the metal-free cascade spirocyclization resulting in the dual oxidative C?O bond formation. (Figure presented.).
Studies towards hypoxia-activated prodrugs of PARP inhibitors
Dickson, Benjamin D.,Wong, Way Wua,Wilson, William R.,Hay, Michael P.
, (2019/05/02)
Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity. We have investigated potential HAPs of model PARPi in which we attach a bioreducible “trigger” to the amide nitrogen, thereby blocking key binding interactions. A representative example showed promise in abrogating PARPi enzymatic activity in a biochemical assay, with a ca. 160-fold higher potency of benzyl phthalazinone 4 than the corresponding model HAP 5, but these N-alkylated compounds did not release the PARPi upon one-electron reduction by radiolysis. Therefore, we extended our investigation to include NU1025, a PARPi that contains a phenol distal to the core binding motif. The resulting 2-nitroimidazolyl ether provided modest abrogation of PARPi activity with a ca. seven-fold decrease in potency, but released the PARPi efficiently upon reduction. This investigation of potential prodrug approaches for PARPi has identified a useful prodrug strategy for future exploration.
