- MODULATORS OF MYOCYTE LIPID ACCUMULATION AND INSULIN RESISTANCE AND METHODS OF USE THEREOF
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Formulations and methods for reducing blood glucose and/or increasing insulin signaling in a subject have been developed. The formulations include SBI-477 and compounds based on SBI-477 i.e., SBI-477 analogs (collectively, SBI-477 compounds) and/or Mondo family inhibitors, in an effective amount to inhibit intracellular lipid accumulation and/or increase cellular glucose uptake when compared to levels in a control subject not administered the composition. Also disclosed are methods of reducing intracellular lipid accumulation and/or increase glucose uptake in a subject in need thereof. The method includes administering to the subject an effective amount of SBI-477 compounds and/or Mondo family inhibitor to reducing intracellular lipid accumulation and/or increase glucose uptake in the subject. Also disclosed are method for treating one or more Myc-driven cancers, including neuroblastoma, lung squamous cell carcinoma/lung adenocarcinoma, liver hepatocellular carcinoma, colon adenocarcinoma, acute myeloid leukemia, and breast invasive carcinoma.
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Page/Page column 112; 113
(2017/02/24)
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- 2,4,5-Trisubstituted thiazole derivatives as HIV-1 NNRTIs effective on both wild-type and mutant HIV-1 reverse transcriptase: Optimization of the substitution of positions 4 and 5
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In our previous work, novel 2,4,5-trisubstituted thiazole derivatives (TSTs) were synthesized, and their activities were evaluated against HIV-1 reverse transcriptase. Some interesting results were obtained, which led us to a new discovery regarding these TSTs. In the present study, 21 new 2,4,5-trisubstituted thiazole derivatives were rationally designed and synthesized as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) in accordance with our previous study. Among the synthesized target compounds, compounds 14, 16, 17, and 19 showed more potent inhibitory activities against HIV-1 with an IC50value of 0.010?μM. Compounds 4, 9, 10, 11, 13 and 16 were further tested on nine NNRTI-resistant HIV-1 strains, and all of these compounds exhibited inhibitory effects. A molecular docking study was conducted, and the results showed a consistent and stable binding mode for the typical compounds. These results have provided deeper insights and SAR of these types of NNRTIs.
- Xu, Zhongliang,Guo, Jiamei,Yang, Ying,Zhang, Mengdi,Ba, Mingyu,Li, Zhenzhong,Cao, Yingli,He, Ricai,Yu, Miao,Zhou, Hua,Li, Xiaoxi,Huang, Xiaoshan,Guo, Ying,Guo, Changbin
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p. 309 - 316
(2016/08/04)
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- Discovery of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists
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A novel series of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as RORγt inverse agonists was discovered. Binding mode analysis of a RORγt partial agonist (2c) revealed by co-crystal structure in RORγt LBD suggests that the inverse agonists do not directly interfere with the interaction between H12 and the RORγt LBD. Detailed SAR exploration led to identification of potent RORγt inverse agonists such as 3m with a pIC50 of 8.0. Selected compounds in the series showed reasonable activity in Th17 cell differentiation assay as well as low intrinsic clearance in mouse liver microsomes.
- Wang, Yonghui,Yang, Ting,Liu, Qian,Ma, Yingli,Yang, Liuqing,Zhou, Ling,Xiang, Zhijun,Cheng, Ziqiang,Lu, Sijie,Orband-Miller, Lisa A.,Zhang, Wei,Wu, Qianqian,Zhang, Kathleen,Li, Yi,Xiang, Jia-Ning,Elliott, John D.,Leung, Stewart,Ren, Feng,Lin, Xichen
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p. 5293 - 5302
(2015/11/10)
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- 2,4,5-Trisubstituted thiazole derivatives: A novel and potent class of non-nucleoside inhibitors of wild type and mutant HIV-1 reverse transcriptase
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Novel 2,4,5-trisubstituted thiazole derivatives (TSTs) were designed and synthesized as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Among the thirty-eight synthesized target compounds, thirty TSTs showed potent inhibition against HIV-1 replication in wild type HIV-1 at submicromolar concentrations (from 0.046 to 9.59 μM). Compounds 21, 23 and 24 were also tested on seven NNRTI-resistant HIV-1 strains, and all exhibited inhibitory effects with fold changes in IC50 ranging from 2.6 to 111, which were better than those of nevirapine (15.6-fold-371-fold). Docking simulations of compound 24 revealed a reasonable mechanism for the binding mode, and three-dimensional quantitative structure activity relationship (3-DQSAR) studies on this novel series of TST further elucidated the structure-activity relationship (SAR). The results suggested the great potential of TSTs as a novel class of NNRTIs with antiviral efficacy and a good resistance profile.
- Xu, Zhongliang,Ba, Mingyu,Zhou, Hua,Cao, Yingli,Tang, Chaojun,Yang, Ying,He, Ricai,Liang, Yu,Zhang, Xuemei,Li, Zhenzhong,Zhu, Lihong,Guo, Ying,Guo, Changbin
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- Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors
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Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration.
- Wang, Yonghui,Cai, Wei,Zhang, Guifeng,Yang, Ting,Liu, Qian,Cheng, Yaobang,Zhou, Ling,Ma, Yingli,Cheng, Ziqiang,Lu, Sijie,Zhao, Yong-Gang,Zhang, Wei,Xiang, Zhijun,Wang, Shuai,Yang, Liuqing,Wu, Qianqian,Orband-Miller, Lisa A.,Xu, Yan,Zhang, Jing,Gao, Ruina,Huxdorf, Melanie,Xiang, Jia-Ning,Zhong, Zhong,Elliott, John D.,Leung, Stewart,Lin, Xichen
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supporting information
p. 692 - 702
(2014/01/23)
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- COMPOUNDS USEFUL AS RETINOID-RELATED ORPHAN RECEPTOR GAMMA MODULATORS
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Disclosed are retinoid-related orphan receptor gamma (RORγ) modulators of Formula (I) and their use in the treatment of diseases mediated by RORγ, wherein the radicals have the meanings as defined in the invention.
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- AMIDE COMPOUND
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The present invention relate to a compound represented by the formula (I) or (II) wherein ring A is an optionally substituted ring (the ring should not be pyrrolidine, piperidine and piperazine), ring B is an optionally substituted aromatic ring, ring D is an optionally substituted ring, R1 and R2 are each independently a hydrogen atom or a substituent, R3 is a hydrogen atom or a C1-6 alkyl group, or R3 is bonded to ring A to form a non-aromatic ring, ring Aa is an optionally substituted aromatic hydrocarbon, Y is CH or N, Ra1 is an optionally substituted hydrocarbon group, and Ra2 and Ra3 are each independently a hydrogen atom or a substituent, or a salt thereof. The present invention provides a compound having a DGAT inhibitory activity, which is useful for the treatment or amelioration of diseases or pathologies caused by high expression or high activation of DGAT.
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- AMIDE COMPOUND
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Disclosed is a compound represented by the formula (I) or (II) below, or a salt thereof. [In the formulae, ring A represents an optionally substituted ring (which is not a pyrrolidine, piperidine or piperazine); ring B represents an optionally substituted aromatic ring; ring D represents an optionally substituted ring; R1 and R2 independently represent a hydrogen atom or a substituent; R3 represents a hydrogen atom or a C1-6 alkyl group, or alternatively it combines with the ring A to form a non-aromatic ring; ring Aa represents an optionally substituted aromatic hydrocarbon; Y represents CH or N; Ra1 represents an optionally substituted hydrocarbon group; and Ra2 and Ra3 independently represent a hydrogen atom or a substituent.] The compound has a DGAT inhibitory effect and is useful for treatment or improvement of diseases or conditions caused by high expression or high activation of DGAT.
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Page/Page column 77
(2008/06/13)
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