56456-50-9Relevant articles and documents
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.
RORγ MODULATORS
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Page/Page column 21; 38, (2018/04/13)
The invention provides an RORγ receptor agonist comprising a compound of formula (I), wherein the variables are as defined herein. These compounds are analogous to known RORγ receptor antagonists. The invention further provides a method of activating -the nuclear receptor RORγ, comprising -contacting the RORγ with an effective amount or concentration of a compound of the invention; and a method of treating cancer in a patient, comprising administering to the patient an effective dose of a compound of the invention.
N-Arylsulfonyl Indolines as Retinoic Acid Receptor-Related Orphan Receptor γ (RORγ) Agonists
Doebelin, Christelle,Patouret, Rémi,Garcia-Ordonez, Ruben D.,Chang, Mi Ra,Dharmarajan, Venkatasubramanian,Kuruvilla, Dana S.,Novick, Scott J.,Lin, Li,Cameron, Michael D.,Griffin, Patrick R.,Kamenecka, Theodore M.
supporting information, p. 2607 - 2620 (2016/12/09)
The nuclear retinoic acid receptor-related orphan receptor γ (RORγ; NR1F3) is a key regulator of inflammatory gene programs involved in T helper 17 (TH17) cell proliferation. As such, synthetic small-molecule repressors (inverse agonists) targeting RORγ have been extensively studied for their potential as therapeutic agents for various autoimmune diseases. Alternatively, enhancing TH17 cell proliferation through activation (agonism) of RORγ may boost an immune response, thereby offering a potentially new approach in cancer immunotherapy. Herein we describe the development of N-arylsulfonyl indolines as RORγ agonists. Structure–activity studies reveal a critical linker region in these molecules as the major determinant for agonism. Hydrogen/deuterium exchange coupled to mass spectrometry (HDX-MS) analysis of RORγ–ligand complexes help rationalize the observed results.
Synthesis of structurally diverse diarylketones through the diarylmethyl sp3 C-H oxidation
He, Chao,Zhang, Xiaohui,Huang, Ruofeng,Pan, Jing,Li, Jiaqiang,Ling, Xuege,Xiong, Yan,Zhu, Xiangming
supporting information, p. 4458 - 4462 (2014/08/05)
Under open-flask conditions, an efficient method to assemble a series of diversely functionalized diarylketones in the presence of commercially available NBS has been developed. Yields of up to 99% have been achieved employing diarylmethanes as starting material. Based on 18O-labeled experiment, the addition of stoichiometric water eventually leads to excellent yields in all carbonylation cases.
