- Design, synthesis and biological evaluation of arylpyridin-2-yl guanidine derivatives and cyclic mimetics as novel msk1 inhibitors. An application in an asthma model
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Mitogen-and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase, taking part in the activation pathway of the pro-inflammatory transcription factor NF-kB and is demonstrating a therapeutic target potential in inflammatory diseases such as asthma, psoriasis and atherosclerosis. To date, few MSK1 inhibitors were reported. In order to identify new MSK1 inhibitors, a screening of a library of low molecular weight compounds was performed, and the results highlighted the 6-phenylpyridin-2-yl guanidine (compound 1a, IC50~18 μM) as a starting hit for structure-activity relationship study. Derivatives, homologues and rigid mimetics of 1a were designed, and all synthesized compounds were evaluated for their inhibitory activity towards MSK1. Among them, the non-cytotoxic 2-aminobenzimidazole 49d was the most potent at inhibiting significantly: (i) MSK1 activity, (ii) the release of IL-6 in inflammatory conditions in vitro (IC50~2 μM) and (iii) the inflammatory cell recruitment to the airways in a mouse model of asthma.
- Bihel, Frédéric,Bollenbach, Maud,Bourguignon, Jean-Jacques,Camelin, Guillaume,Daubeuf, Fran?ois,Frossard, Nelly,Nemska, Simona,Obrecht, Adeline,Rognan, Didier,Schmitt, Martine,Villa, Pascal,Wagner, Patrick
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- Cyclic amidino agents useful as nitric oxide synthase inhibitors
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The current invention discloses useful amidino derivative useful as nitric oxide synthase inhibitors.
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- Substituted 2-aminopyridines as inhibitors of nitric oxide synthase
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Substituted 2-aminopyridine compounds of Formula (I) and pharmaceutically acceptable salts which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders. STR1
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- Azepine derivatives useful as nitric oxide synthase inhibitors
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The current invention discloses azepine derivatives useful as nitric oxide synthase inhibitors.
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- Substituted 2-iminopiperidines as inhibitors of human nitric oxide synthase isoforms
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A series of analogues of 2-iminopiperidine have been prepared and shown to be potent inhibitors of the human nitric oxide synthase (NOS) isoforms. Methyl substitutions on the 4-position (3) or 4- and 6-positions (8) afforded the most potent analogues. These compounds exhibited IC50 values of 0.1 and 0.08 μM, respectively, for hiNOS inhibition. Substitution with cyclohexylmethyl at the 6-position (13) afforded an inhibitor that showed the best selectivity for hiNOS versus heNOS (heNOS IC50/hiNOS IC50 = 64). Following oral administration, inhibitors were found to decrease serum nitrite/nitrate levels in an in vivo rat endotoxin assay. This series of 2- iminopiperidines were prepared via the described synthetic methodologies. The effect of ring substitutions on potency and selectivity for this class of cyclic amidines as NOS inhibitors is described.
- Webber, R. Keith,Metz, Suzanne,Moore, William M.,Connor, Jane R.,Currie, Mark G.,Fok, Kam F.,Hagen, Timothy J.,Hansen Jr., Donald W.,Jerome, Gina M.,Manning, Pamela T.,Pitzele, Barnett S.,Toth, Mihaly V.,Trivedi, Mahima,Zupec, Mark E.,Siong Tjoeng
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