- Development of the First Two-Pore Domain Potassium Channel TWIK-Related K+ Channel 1-Selective Agonist Possessing in Vivo Antinociceptive Activity
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The TWIK-related K+ channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs, suggesting that activation of TREK-1 could result in pain inhibition. Here, we report the synthesis of a series of substituted acrylic acids (1-54) based on our previous work with caffeate esters. The analogues were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid-induced writhing and hot plate assays), leading to the identification of a series of novel molecules able to activate TREK-1 and displaying potent antinociceptive activity in vivo. Furyl analogue 36 is the most promising of the series.
- Vivier, Delphine,Soussia, Ismail Ben,Rodrigues, Nuno,Lolignier, Stéphane,Devilliers, Ma?ly,Chatelain, Franck C.,Prival, Laetitia,Chapuy, Eric,Bourdier, Geoffrey,Bennis, Khalil,Lesage, Florian,Eschalier, Alain,Busserolles, Jér?me,Ducki, Sylvie
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supporting information
p. 1076 - 1088
(2017/02/19)
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- Thiophene inhibitors of PDE4: Crystal structures show a second binding mode at the catalytic domain of PDE4D2
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PDE4 inhibitors have been identified as therapeutic targets for a variety of conditions, particularly inflammatory diseases. We have serendipitously identified a novel class of phosphodiesterase 4 (PDE4) inhibitor during a study to discover antagonists of the parathyroid hormone receptor. X-ray crystallographic studies of PDE4D2 complexed to four potent inhibitors reveal the atomic details of how they inhibit the enzyme and a notable contrast to another recently reported thiophene-based inhibitor.
- Nankervis, Jacob L.,Feil, Susanne C.,Hancock, Nancy C.,Zheng, Zhaohua,Ng, Hooi-Ling,Morton, Craig J.,Holien, Jessica K.,Ho, Patricia W.M.,Frazzetto, Mark M.,Jennings, Ian G.,Manallack, David T.,John Martin,Thompson, Philip E.,Parker, Michael W.
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supporting information; experimental part
p. 7089 - 7093
(2012/01/06)
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- A new class of small molecule RNA polymerase inhibitors with activity against Rifampicin-resistant Staphylococcus aureus1
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The RNA polymerase holoenzyme is a proven target for antibacterial agents. A high-throughput screening program based on this enzyme from Staphylococcus aureus had previously identified a 2-ureidothiophene-3-carboxylate as a low micromolar inhibitor. An investigation of the relationships between the structures of this class of compounds and their inhibitory- and antibacterial activities is described here, leading to a set of potent RNA polymerase inhibitors with antibacterial activity. Characterization of this bioactivity, including studies of the mechanism of action, is provided, highlighting the power of the reverse chemical genetics approach in providing tools to inhibit the bacterial RNA polymerase.
- Arhin, Francis,Belanger, Odette,Ciblat, Stephane,Dehbi, Mohammed,Delorme, Daniel,Dietrich, Evelyne,Dixit, Dilip,Lafontaine, Yanick,Lehoux, Dario,Liu, Jing,McKay, Geoffrey A.,Moeck, Greg,Reddy, Ranga,Rose, Yannick,Srikumar, Ramakrishnan,Tanaka, Kelly S.E.,Williams, Daniel M.,Gros, Philippe,Pelletier, Jerry,Parr Jr., Thomas R.,Far, Adel Rafai
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p. 5812 - 5832
(2007/10/03)
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