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1.
J Med Chem ; 64(9): 5905-5930, 2021 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-33904304

RESUMEN

There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series' structure-activity relationships.


Asunto(s)
Diseño de Fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/química , Proteínas Protozoarias/metabolismo , Animales , Antiprotozoarios/química , Antiprotozoarios/metabolismo , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Sitios de Unión , Línea Celular , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Leishmania donovani/efectos de los fármacos , Leishmania donovani/metabolismo , Leishmaniasis Visceral/tratamiento farmacológico , Leishmaniasis Visceral/parasitología , Ratones , Simulación de Dinámica Molecular , Complejo de la Endopetidasa Proteasomal/química , Inhibidores de Proteasoma/metabolismo , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Subunidades de Proteína/química , Subunidades de Proteína/metabolismo , Proteínas Protozoarias/química , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Solubilidad , Relación Estructura-Actividad
2.
Proc Natl Acad Sci U S A ; 116(19): 9318-9323, 2019 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-30962368

RESUMEN

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the ß5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the ß4 and ß5 proteasome subunits. This induced pocket exploits ß4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.


Asunto(s)
Antiprotozoarios/administración & dosificación , Leishmania donovani/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Leishmaniasis Visceral/diagnóstico por imagen , Inhibidores de Proteasoma/administración & dosificación , Proteínas Protozoarias/antagonistas & inhibidores , Animales , Antiprotozoarios/química , Sitios de Unión , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Leishmania donovani/química , Leishmania donovani/enzimología , Leishmania infantum/química , Leishmania infantum/enzimología , Leishmaniasis Visceral/parasitología , Masculino , Ratones , Complejo de la Endopetidasa Proteasomal/química , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/química , Conformación Proteica , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo
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