RESUMEN
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Pirimidinas/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Enfermedad de Chagas/parasitología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Pirimidinas/administración & dosificación , Pirimidinas/química , Relación Estructura-Actividad , Tripanocidas/administración & dosificación , Tripanocidas/químicaRESUMEN
BACKGROUND: Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim. RESULTS: We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection. CONCLUSION: High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.
Asunto(s)
Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Administración Oral , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/mortalidad , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Modelos Animales de Enfermedad , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Pruebas de Sensibilidad Parasitaria , Ratas , Relación Estructura-Actividad , Tasa de Supervivencia , Factores de Tiempo , Tripanocidas/química , Tripanocidas/uso terapéuticoRESUMEN
A scaffold hopping exercise undertaken to expand the structural diversity of the fenarimol series of anti-Trypanosoma cruzi (T. cruzi) compounds led to preparation of simple 1-[phenyl(pyridin-3-yl)methyl]piperazinyl analogues of fenarimol which were investigated for their ability to inhibit T. cruzi in vitro in a whole organism assay. A range of compounds bearing amide, sulfonamide, carbamate/carbonate and aryl moieties exhibited low nM activities and two analogues were further studied for in vivo efficacy in a mouse model of T. cruzi infection. One compound, the citrate salt of 37, was efficacious in a mouse model of acute T. cruzi infection after once daily oral dosing at 20, 50 and 100 mg/kg for 5 days.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Piperazinas/química , Piperazinas/uso terapéutico , Tripanocidas/química , Tripanocidas/uso terapéutico , Trypanosoma cruzi/efectos de los fármacos , Administración Oral , Animales , Enfermedad de Chagas/parasitología , Diseño de Fármacos , Humanos , Ratones , Piperazina , Piperazinas/administración & dosificación , Piperazinas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Relación Estructura-Actividad , Tripanocidas/administración & dosificación , Tripanocidas/farmacologíaRESUMEN
We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi ( T. cruzi ), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC(50)s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Pirimidinas/química , Pirimidinas/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Línea Celular , Enfermedad de Chagas/metabolismo , Enfermedad de Chagas/parasitología , Modelos Animales de Enfermedad , Cromatografía de Gases y Espectrometría de Masas , Concentración 50 Inhibidora , Masculino , Ratones , Resonancia Magnética Nuclear Biomolecular , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/farmacocinéticaRESUMEN
Cell permeable carrier peptides are currently of interest for their potential to improve the delivery of bioactive molecules into cells and to specific cellular compartments. We have investigated the activity of a derivative of the antiandrogen drug, bicalutamide, attached to the cell-permeable carrier peptide penetratin(R). We have used both disulfide (labile) and thioether (nonlabile) linkages to attach the bicalutamide derivative to the peptide in order to assess whether one type of chemistry has advantages over the other. In addition we have added a nuclear localization sequence (NLS) to the carrier peptide to investigate whether localization of the drug to the nucleus of the cell affects the activity of the drug. Biotin-labeled peptides were used to demonstrate that the carrier peptide is rapidly accumulated inside cultured cells, and that the incorporation of an NLS in the sequence results in its nuclear targeting. The bicalutamide derivative linked to carrier peptides via a disulfide-linkage exerted no greater antiproliferative effect in LNCaP cells, than the bicalutamide derivative alone. The bicalutamide derivative linked to the carrier peptide by a non-labile thioether linkage showed a similar activity profile. When the construct includes a nuclear targeting sequence, however, a markedly increased antiproliferative effect was observed. This study has thus shown that the activity of bicalutamide may be enhanced by the nonlabile attachment of a cell-permeable and nuclear-targeted peptide, which has implications for the development of novel antiandrogens for the treatment of prostate cancer.