- Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties
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To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = ?0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.
- Fersing, Cyril,Boudot, Clotilde,Paoli-Lombardo, Romain,Primas, Nicolas,Pinault, Emilie,Hutter, Sébastien,Castera-Ducros, Caroline,Kabri, Youssef,Pedron, Julien,Bourgeade-Delmas, Sandra,Sournia-Saquet, Alix,Stigliani, Jean-Luc,Valentin, Alexis,Azqueta, Amaya,Muruzabal, Damián,Destere, Alexandre,Wyllie, Susan,Fairlamb, Alan H.,Corvaisier, Sophie,Since, Marc,Malzert-Fréon, Aurélie,Di Giorgio, Carole,Rathelot, Pascal,Azas, Nadine,Courtioux, Bertrand,Vanelle, Patrice,Verhaeghe, Pierre
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- HETEROCYCLIC COMPOUND
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Provided is a heterocyclic compound that may have a GCN2 inhibitory action, and is expected to be useful for the prophylaxis or treatment of GCN2 associated diseases including cancer and the like. A compound represented by the formula (I): wherein each symbol is as described in the DESCRIPTION, or a salt thereof.
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Paragraph 1139; 1140; 1141
(2019/06/17)
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- BICYCLIC PIPERAZINE COMPOUNDS
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Bicyclic piperazine compounds of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Paragraph 0195; 0196; 0197
(2013/05/21)
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- S PIRO [CHROMAN - 4, 4 ' - IMIDAZOL] ONES AS BETA - SECRETASE INHIBITORS
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The invention provides novel spirochroman compounds of Formulas I and II that inhibit β-secretase cleavage of APP and are useful as therapeutic agents for treating neurodegenerative diseases.
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Page/Page column 74
(2011/06/26)
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