RESUMO
Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class.
Assuntos
Doença de Chagas/tratamento farmacológico , Nitroimidazóis/química , Nitroimidazóis/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos , Camundongos , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/fisiologiaRESUMO
Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα enzyme potency and good cellular potency in two human derived cell lines. The overall results suggest a preference for linear and somewhat flexible solubilizing functions. From this series, compound 16, also known as SN32976, was selected for advanced preclinical evaluation.
Assuntos
Fosfatidilinositol 3-Quinases/química , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Sulfonamidas/química , Triazinas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Concentração Inibidora 50 , Camundongos , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Transplante HeterólogoRESUMO
Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6 R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads ( R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds ( R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.
Assuntos
Antiparasitários/síntese química , Antiparasitários/farmacologia , Leishmaniose Visceral/tratamento farmacológico , Oxazinas/síntese química , Oxazinas/farmacologia , Animais , Antiparasitários/farmacocinética , Permeabilidade da Membrana Celular , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Cricetinae , Citocromo P-450 CYP3A/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Canal de Potássio ERG1/antagonistas & inibidores , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/crescimento & desenvolvimento , Leishmania infantum/efeitos dos fármacos , Leishmania infantum/crescimento & desenvolvimento , Leishmaniose Visceral/parasitologia , Mesocricetus , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
It is suggested that our current understanding of the role of nutrients in maintaining genomic stability might be strategically employed alongside current chemotherapy, in order to prevent the emergence of drug resistant tumors and optimize medicinal chemistry approaches.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Instabilidade Genômica/efeitos dos fármacos , Microbiota , Fenômenos Fisiológicos da Nutrição , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/prevenção & controle , Dietoterapia/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Microbioma Gastrointestinal , Humanos , Microbiota/efeitos dos fármacos , Microbiota/genética , Nutrigenômica/métodos , Fenômenos Fisiológicos da Nutrição/genética , Vitamina D/farmacologia , Vitamina D/fisiologiaRESUMO
High-throughput screening of a small-molecule library identified a 5-triazolo-2-arylpyridazinone as a novel inhibitor of the important glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3). Such inhibitors are of interest due to PFKFB3's control of the important glycolytic pathway used by cancer cells to generate ATP. A series of analogues was synthesized to study structure-activity relationships key to enzyme inhibition. Changes to the triazolo or pyridazinone rings were not favoured, but limited-size substitutions on the aryl ring provided modest increases in potency against the enzyme. Selected analogues and literature-described inhibitors were evaluated for their ability to suppress the glycolytic pathway, as detected by a decrease in lactate production, but none of these compounds demonstrated such suppression at non-cytotoxic concentrations.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fosfofrutoquinase-2/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos/métodos , Glicólise/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piridazinas/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
We have made a novel series of pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors, and demonstrated their selectivity for the p110α isoform over the other Class Ia PI3 kinases. We investigated the SAR around the pyrazolo[1,5-a]pyridine ring system, and found compound 5x to be a particularly potent example (p110α IC(50) 0.9nM). This compound inhibits cell proliferation and phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity, and showed in vivo activity in an HCT-116 human xenograft model.
Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Pirazóis/química , Piridinas/química , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/síntese química , Piridinas/farmacologia , Transplante HeterólogoRESUMO
A structure-activity study of several new synthetic analogues of the avocado-produced toxin persin has been conducted, with compounds being evaluated for their cytostatic and pro-apoptotic effects in human breast cancer cells. A 4-pyridinyl derivative demonstrated activity comparable to that of the natural product, suggesting future directions for exploration of structure-activity relationships.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Persea/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Álcoois Graxos/síntese química , Feminino , Humanos , Extratos Vegetais/síntese química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of biphenyl analogues of the new tuberculosis drug PA-824 was prepared, primarily by coupling the known (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol with iodobenzyl halides, followed by Suzuki coupling of these iodides with appropriate arylboronic acids or by assembly of the complete biaryl side chain prior to coupling with the above alcohol. Antitubercular activity was determined under both replicating (MABA) and nonreplicating (LORA) conditions. para-Linked biaryls were the most active, followed by meta-linked and then ortho-linked analogues. A more detailed study of a larger group of para-linked analogues showed a significant correlation between potency (MABA) and both lipophilicity (CLOGP) and the electron-withdrawing properties of terminal ring substituents ( summation operatorsigma). Selected compounds were evaluated for their efficacy in a mouse model of acute Mycobacterium tuberculosis infection. In vivo activity correlated well with the stability of compounds to microsomal metabolism. Three compounds bearing combinations of lipophilic, electron-withdrawing groups achieved >200-fold higher efficacies than the parent drug.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Nitroimidazóis/síntese química , Nitroimidazóis/farmacologia , Animais , Antituberculosos/química , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Nitroimidazóis/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Drug discovery and development, from an initial disease treatment concept to a new drug application (NDA), is a complex, lengthy and expensive process. In this review we discuss the key stages of drug discovery and early development, including target identification and validation, assay development and screening, confirmed hits to leads, lead optimization, and progressing development candidates to an investigational new drug (IND) filing. We also provide particular examples of how this process is beginning to assist in the development of small molecule treatments for tuberculosis, by summarizing the status of the clinical development of several newer classes of drugs. These include the fluoroquinolones, oxazolidinones, diarylquinolines, and nitroimidazo-oxazoles and -oxazines.
Assuntos
Antituberculosos/uso terapêutico , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/farmacologia , Desenho de Fármacos , Avaliação de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Drogas em Investigação/uso terapêutico , Humanos , Mycobacterium tuberculosis/efeitos dos fármacosRESUMO
Symmetrical dimers of lipophilic intercalating chromophores linked by cation-containing chains have recently been shown to have broad-spectrum in vivo anticancer activity. We report the preparation and evaluation of a series of both symmetric and unsymmetric dimers of a variety of intercalating chromophores of varied DNA binding strength, including naphthalimides, acridines, phenazines, oxanthrenes and 2-phenylquinolines. The unsymmetrical dimers were prepared by sequential coupling of the chromophores to linkers with selectively protected primary terminal amines to ensure high yields and unequivocal product. Protection of the internal (secondary) amines as BOC derivatives was used to ensure complete structural specificity, and was also an aid to the purification of these very polar compounds. The growth inhibitory abilities (as IC(50) values) of the compounds in a range of cell lines showed that the nature of the linker chain was important, and independent of the nature of the chromophore, with compounds containing the dicationic linker [-(CH2)2NH(CH2)2NH(CH2)2-] being on average 30-fold more potent than the corresponding compounds containing the monocationic linker [-(CH2)3NMe(CH2)3-]. However, the chromophores also play a role in determining biological activity, with the cytotoxicities of symmetric and unsymmetric dicationic dimers correlating with the overall DNA binding abilities of the chromophores.