- Structure-Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators
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Free fatty acid receptor 3 (FFA3, previously GPR41) is activated by short-chain fatty acids, mediates health effects of the gut microbiota, and is a therapeutic target for metabolic and inflammatory diseases. The shortage of well-characterized tool compounds has however impeded progress. Herein, we report structure-activity relationship of an allosteric modulator series and characterization of physicochemical and pharmacokinetic properties of selected compounds, including previous and new tools. Two representatives, 57 (TUG-1907) and 63 (TUG-2015), showed improved solubility and preserved potency. Of these, 57, with EC50 = 145 nM and a solubility of 33 μM, showed high clearance in vivo but is a preferred tool in vitro. In contrast, 63, with EC50 = 162 nM and a solubility of 9 μM, showed lower clearance and seems better suited for in vivo studies. Using 57, we demonstrate for the first time that FFA3 activation leads to calcium mobilization in murine dorsal root ganglia.
- Ulven, Elisabeth Rexen,Quon, Tezz,Sergeev, Eugenia,Barki, Natasja,Brvar, Matjaz,Hudson, Brian D.,Dutta, Palash,Hansen, Anders H?jgaard,Bielefeldt, Line O.,Tobin, Andrew B.,McKenzie, Christine J.,Milligan, Graeme,Ulven, Trond
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p. 3577 - 3595
(2020/04/30)
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- Selective exploitation of acetoacetate carbonyl groups using imidazolium based ionic liquids: synthesis of 3-oxo-amides and substituted benzimidazoles
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An unprecedented Br?nsted base ionic liquid tuned selective aminolysis of ester carbonyl of acetoacetates is demonstrated to achieve acetoacetamide derivatives. Other imidazolium ionic liquid performs an efficient cyclization catalysis involving acetoacetate-carbonyl groups and o-phenylenediamine at elevated temperature to produce benzimidazoles via C–C bond cleavage of intermediate 1,5-benzodiazepinones under solvent-free conditions.
- Chakraborty, Ankita,Majumdar, Swapan,Maiti, Dilip K.
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p. 3298 - 3302
(2016/07/11)
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- A Facile Synthesis of 5-Phenyl-Dibenzo[b, g][1,8]Napthyridines
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The Vilsmeier Haack heterocyclization of 2-aryl amino-4-phenyl quinolines quinoline yielded the hitherto unknown 5-phenyl-dibenzo[b,g][1,8]naphthyridines in quantitative yield. The synthesis of aryl amines was achieved by the action of anilines on 2-chloro-4-phenyl quinoline, which in turn was sourced through the combes reaction of benzoyl acetanilides.
- Sampathkumar, Natarajan,Murugesh, Arumugam,Rajendran, Subramaniam Parameswaran
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p. 924 - 928
(2016/05/19)
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- Synthesis and anticonvulsant activity of 5-phenyl-[1,2,4]-triazolo[4,3-a] quinolines
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A series of novel 5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline derivatives was synthesized by the cyclization of 2-chloro-4-phenyl-1,2-dihydronaphthalene with formohydrazide. The starting material 2-chloro-4-phenyl-1,2-dihydronaphthalene was synthesized from ethyl-3-oxo-3-phenylpropanoate and substituted aniline. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The maximal electroshock test showed that 7-hexyloxy-5-phenyl-[1,2,4]- triazolo[4,3-a]quinoline 4f was found to be the most potent compound with an ED50 value of 6.5 mg/kg and a protective index (PI = ED 50/TD50) value of 35.1, which was much higher than the PI of the reference drug phenytoin.
- Guan, Li-Ping,Jin, Qing-Hao,Wang, Shou-Feng,Li, Fu-Nan,Quan, Zhe-Shan
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scheme or table
p. 774 - 779
(2009/04/14)
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