- 6-Methyl-7-Aryl-7-Deazapurine Nucleosides as Anti-Trypanosoma cruzi Agents: Structure-Activity Relationship and in vivo Efficacy
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Chagas disease is a tropical infectious disease resulting in progressive organ-damage and currently lacks efficient treatment and vaccine options. The causative pathogen, Trypanosoma cruzi, requires uptake and processing of preformed purines from the host because it cannot synthesize these de novo, instigating the evaluation of modified purine nucleosides as potential trypanocides. By modifying the pyrimidine part of a previously identified 7-aryl-7-deazapurine nucleoside, we found that substitution of a 6-methyl for a 6-amino group allows retaining T. cruzi amastigote growth inhibitory activity but confers improved selectivity towards mammalian cells. By keeping the 6-methyl group unaltered, and introducing different 7-aryl groups, we identified several analogues with sub-micromolar antitrypanosomal activity. The 7-(4-chlorophenyl) analogue 14, which was stable in microsomes, was evaluated in an acute mouse model. Oral administration of 25 mg/kg b.i.d. suppressed peak parasitemia and protected mice from infection-related mortality, gave similar reductions as the reference drug of blood parasite loads determined by qPCR, but as benznidazole failed to induce sterile cure in the short time period of drug exposure (5 days).
- Lin, Cai,Ferreira de Almeida Fiuza, Ludmila,Cardoso Santos, Camila,Ferreira Nunes, Daniela,Cruz Moreira, Otacílio,Bouton, Jakob,Karalic, Izet,Maes, Louis,Caljon, Guy,Hulpia, Fabian,de Nazaré C. Soeiro, Maria,Van Calenbergh, Serge
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p. 2231 - 2253
(2021/05/18)
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- PYRROLO[2,3-B]PYRIDIN DERIVATIVES AS INHIBITORS OF INFLUENZA VIRUS REPLICATION
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Provided herein are compounds of Formula A, B or C that can inhibit the replication of influenza viruses, reduce the amount of influenza viruses, and/or treat influenza.
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Paragraph 00364
(2020/02/16)
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- PYRROLOPYRIMIDINE DERIVATIVES USEFUL AS INHIBITORS OF INFLUENZA VIRUS REPLICATION
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Methods of inhibiting the replication of influenza viruses in a biological sample or patient, of reducing the amount of influenza viruses in a biological sample or patient, and of treating influenza in a patient, comprises administering to said biological sample or patient a safe and effective amount of a compound represented by any of Formulas l-lll, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprises a safe and effective amount of such a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
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Paragraph 00384
(2018/11/22)
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- SODIUM CHANNEL BLOCKERS
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The present invention relates to a compound having a blocking effect against sodium ion channels, particularly Nav 1.7, a preparation method thereof and use thereof. The compound represented by the Formula 1 or a pharmaceutically acceptable salt, hydrate,
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Page/Page column 45-46
(2016/09/22)
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- COMPOUNDS, COMPOSITIONS, AND THERAPEUTIC USES THEREOF
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The invention relates to compounds, pharmaceutical compositions and medicaments comprising such compounds, and the use of these compounds, compositions, and medicaments in methods of treating a variety of diseases and disorders.
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Paragraph 0230
(2014/01/17)
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- AZAINDOLES AS JANUS KINASE INHIBITORS
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The present invention provides compounds of formula I: or a pharmaceutically acceptable salt thereof. Compounds of formula I are inhibitors of Janus kinases and as such are useful for the treatment of various diseases and conditions mediated by said enzym
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