- Selective angiotensin II AT2 receptor agonists: Arylbenzylimidazole structure-activity relationships
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Structural alterations in the 2- and 5-positions of the first drug-like selective angiotensin II AT2 receptor agonist (1) have been performed. The imidazole ring system was proven to be a strong determinant for the AT2 selectivity, and with few exceptions all variations gave good AT2 receptor affinities and with retained high AT 2/AT1 selectivities. On the contrary to the findings with AT1 receptor agonists, the impact of structural modifications in the 5-position of the AT2 selective compounds were less pronounced regarding activation of the AT2 receptor. The butyloxyphenyl (56) and the propylthienyl (50) derivatives were found to exert a high agonistic effect as deduced from their capacity to induce neurite elongation in neuronal cells, as does angiotensin II.
- Wu, Xiongyu,Wan, Yiqian,Mahalingam,Murugaiah,Plouffe, Bianca,Botros, Milad,Karlén, Anders,Hallberg, Mathias,Gallo-Payet, Nicole,Alterman, Mathias
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Read Online
- Discovery of N-Arylsulfonyl-Indole-2-Carboxamide Derivatives as Potent, Selective, and Orally Bioavailable Fructose-1,6-Bisphosphatase Inhibitors - Design, Synthesis, in Vivo Glucose Lowering Effects, and X-ray Crystal Complex Analysis
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Liver fructose-1,6-bisphosphatase (FBPase) is a key enzyme in the gluconeogenesis pathway. Inhibiting FBPase activity represents a potential treatment for type 2 diabetes mellitus. A series of novel N-arylsulfonyl-4-arylamino-indole-2-carboxamide derivatives have been disclosed as FBPase inhibitors. Through extensive structure-activity relationship investigations, a promising candidate molecule Cpd118 [sodium (7-chloro-4-((3-methoxyphenyl)amino)-1-methyl-1H-indole-2-carbonyl] [(4-methoxyphenyl)sulfonyl)amide] has been identified with high inhibitory activity against human liver FBPase (IC50, 0.029 ± 0.006 μM) and high selectivity relative to the other six AMP-binding enzymes. Importantly, Cpd118 produced significant glucose-lowering effects on both type 2 diabetic KKAy mice and ZDF rats as demonstrated by substantial reductions in the fasting and postprandial blood glucose levels, as well as the HbA1c level. Furthermore, Cpd118 elicited a favorable pharmacokinetic profile with an oral bioavailability of 99.1%. Moreover, the X-ray crystal structure of the Cpd118-FBPase complex was resolved, which revealed a unique binding mode and provided a structural basis for its high potency and selectivity.
- Zhou, Jie,Bie, Jianbo,Wang, Xiaoyu,Liu, Quan,Li, Rongcui,Chen, Hualong,Hu, Jinping,Cao, Hui,Ji, Wenming,Li, Yan,Liu, Shuainan,Shen, Zhufang,Xu, Bailing
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supporting information
p. 10307 - 10329
(2020/11/02)
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- N-acyl sulfamide FBPase inhibitor, preparation method thereof, drug composition and application
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The invention discloses an N-acryl sulfamide FBPase inhibitor of a novel structure, and a preparation method thereof, a drug composition and an application, and particularly relates to an N-acryl sulfamide FBPase inhibitor shown in the formula I, a salt thereof for medicine, a preparation method, a composition comprising one or more compounds, an application of the compound in preparing the FBPase inhibitor or a drug for treating FBPase-related diseases, and an application in preparing a drug for preventing and/or treating diabetes. The formula is shown in the description.
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Paragraph 2380; 2384; 2385
(2017/09/08)
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- ANTIBACTERIAL AGENTS: ARYL MYXOPYRONIN DERIVATIVES
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The invention provides compounds of formula la, lb and Ic: [Formula Ia, Ib, and Ic] and salts thereof, wherein variables are as described in the specification, as well as compositions comprising a compound of formula Ia-Ic, methods of making such compounds, and methods of using such compounds, e.g., as inhibitors of bacterial RNA polymerase and as antibacterial agents.
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Page/Page column 101
(2014/01/09)
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- New FBPase inhibitors for diabetes
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Compounds of formula as well as pharmaceutically acceptable salts and esters thereof, wherein R1 to R3 have the significance given in the application and which can be used in the form of pharmaceutical compositions.
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Page/Page column 15
(2008/06/13)
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- A New Synthesis of Tiger Moth Pheromone, 2-Methylheptadecane
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The synthesis of the title pheromone involves two stepwise acylations at 2 and 5 positions of thiophene, followed by removal of the oxygen function through thioketalation and reductive desulphurization.
- Rao, S. Jagadishwar,Bhalerao, U. T.
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p. 1275 - 1276
(2007/10/02)
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