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1.
Eur J Pharm Sci ; 173: 106163, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35248733

RESUMO

The development of novel candidate molecules for tuberculosis remains challenging, as drug distribution into the target tissue is not fully characterised in preclinical models of infection. Often antitubercular human dose selection is derived from pharmacokinetic data in plasma. Here, we explore whether whole-body physiologically-based pharmacokinetic (PBPK) modelling enables the prediction of lung exposure to anti-tubercular drugs in humans. Whole-body PBPK models were developed for rifampicin, isoniazid, pyrazinamide, and ethambutol using plasma data in mice as basis for the prediction of lung exposure. Model parameters were subsequently used to extrapolate disposition properties from mouse and determine lung:plasma ratio in humans. Model predictions were compared to biopsy data from patients. Predictions were deemed adequate if they fell within two-fold range of the observations. The concentration vs time profiles in lung were adequately predicted in mice. Isoniazid and pyrazinamide lung exposures were predicted to be comparable to plasma levels, whereas ethambutol lung exposure was predicted to be higher than in plasma. Lung:plasma ratio in humans could be reasonably predicted from preclinical data, but was highly dependent on the distribution model. This analysis showed that plasma pharmacokinetics may be used in conjunction with PBPK modelling to derive lung tissue exposure in mice and humans during early lead optimisation phase. However, the impact of uncertainty in predicted tissue exposure due to distribution should be always investigated through a sensitivity analysis when only plasma data is available. Despite these limitations, insight into lung tissue distribution represents a critical step for the dose rationale in tuberculosis patients.


Assuntos
Etambutol , Tuberculose , Animais , Antituberculosos/farmacocinética , Etambutol/farmacocinética , Humanos , Isoniazida , Pulmão , Camundongos , Pirazinamida , Tuberculose/tratamento farmacológico
2.
J Comput Aided Mol Des ; 34(11): 1117-1132, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32833084

RESUMO

There is a pressing need to improve the efficiency of drug development, and nowhere is that need more clear than in the case of neglected diseases like malaria. The peculiarities of pyrimidine metabolism in Plasmodium species make inhibition of dihydroorotate dehydrogenase (DHODH) an attractive target for antimalarial drug design. By applying a pair of complementary quantitative structure-activity relationships derived for inhibition of a truncated, soluble form of the enzyme from Plasmodium falciparum (s-PfDHODH) to data from a large-scale phenotypic screen against cultured parasites, we were able to identify a class of antimalarial leads that inhibit the enzyme and abolish parasite growth in blood culture. Novel analogs extending that class were designed and synthesized with a goal of improving potency as well as the general pharmacokinetic and toxicological profiles. Their synthesis also represented an opportunity to prospectively validate our in silico property predictions. The seven analogs synthesized exhibited physicochemical properties in good agreement with prediction, and five of them were more active against P. falciparum growing in blood culture than any of the compounds in the published lead series. The particular analogs prepared did not inhibit s-PfDHODH in vitro, but advanced biological assays indicated that other examples from the class did inhibit intact PfDHODH bound to the mitochondrial membrane. The new analogs, however, killed the parasites by acting through some other, unidentified mechanism 24-48 h before PfDHODH inhibition would be expected to do so.


Assuntos
Antimaláricos/química , Inibidores Enzimáticos/química , Malária Falciparum/tratamento farmacológico , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Quinolonas/química , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Di-Hidro-Orotato Desidrogenase , Desenho de Fármacos , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Quinolonas/efeitos adversos , Quinolonas/farmacocinética
3.
J Med Chem ; 63(9): 4929-4956, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32248693

RESUMO

Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.


Assuntos
Antimaláricos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Malária Falciparum/tratamento farmacológico , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Pirróis/uso terapêutico , Animais , Antimaláricos/síntese química , Antimaláricos/metabolismo , Antimaláricos/farmacocinética , Linhagem Celular Tumoral , Cristalografia por Raios X , Di-Hidro-Orotato Desidrogenase , Cães , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Masculino , Camundongos SCID , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/enzimologia , Ligação Proteica , Pirróis/síntese química , Pirróis/metabolismo , Pirróis/farmacocinética , Ratos , Relação Estrutura-Atividade
4.
J Med Chem ; 62(3): 1180-1202, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30570265

RESUMO

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.


Assuntos
Leishmaniose Visceral/tratamento farmacológico , Morfolinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Tripanossomicidas/uso terapêutico , Animais , Feminino , Células Hep G2 , Humanos , Leishmania donovani/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Estrutura Molecular , Morfolinas/síntese química , Morfolinas/toxicidade , Testes de Sensibilidade Parasitária , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/toxicidade , Pirazóis/síntese química , Pirazóis/toxicidade , Pirimidinas/síntese química , Pirimidinas/toxicidade , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/toxicidade
5.
J Med Chem ; 61(9): 4213-4227, 2018 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-29665687

RESUMO

Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual blood stage parasites that, together with their in vitro absorption, distribution, metabolism, and excretion (ADME) properties, translated to in vivo efficacy with clearance of parasites in the PfSCID mouse model for malaria within 48 h of treatment.


Assuntos
Descoberta de Drogas , Imidazóis/química , Imidazóis/farmacocinética , Malária/tratamento farmacológico , Plasmodium falciparum/fisiologia , Piridinas/química , Piridinas/farmacocinética , Animais , Modelos Animais de Doenças , Estabilidade de Medicamentos , Canal de Potássio ERG1/metabolismo , Humanos , Imidazóis/metabolismo , Imidazóis/uso terapêutico , Malária/genética , Malária/metabolismo , Camundongos , Piridinas/metabolismo , Piridinas/uso terapêutico , Solubilidade , Relação Estrutura-Atividade , Distribuição Tecidual , Água/química
6.
J Med Chem ; 61(8): 3422-3435, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29589932

RESUMO

Malaria is still one of the most prevalent parasitic infections in the world, with half of the world's population at risk for malaria. The effectiveness of current antimalarial therapies, even that of the most recent class of antimalarial drugs (artemisinin-combination therapies, ACTs), is under continuous threat by the spread of resistant Plasmodium strains. As a consequence, there is still an urgent requirement for new antimalarial drugs. We previously reported the identification of 4(1 H)-pyridones as a novel series with potent antimalarial activities. The low solubility was identified as an issue to address. In this paper, we describe the synthesis and biological evaluation of 4(1 H)-pyridones with potent antimalarial activities in vitro and in vivo and improved pharmacokinetic profiles. Their main structural novelties are the presence of polar moieties, such as hydroxyl groups, and the replacement of the lipophilic phenyl rings with pyridines on their lipophilic side chains.


Assuntos
Antimaláricos/farmacologia , Piridonas/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacocinética , Feminino , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Plasmodium yoelii/efeitos dos fármacos , Piridonas/síntese química , Piridonas/química , Piridonas/farmacocinética , Relação Estrutura-Atividade
7.
Br J Clin Pharmacol ; 84(3): 482-489, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29168205

RESUMO

AIMS: GSK3191607, a novel inhibitor of the Plasmodium falciparum ATP4 (PfATP4) pathway, is being considered for development in humans. However, a key problem encountered during the preclinical evaluation of the compound was its inconsistent pharmacokinetic (PK) profile across preclinical species (mouse, rat and dog), which prevented reliable prediction of PK parameters in humans and precluded a well-founded assessment of the potential for clinical development of the compound. Therefore, an open-label microdose (100 µg, six subjects) first time in humans study was conducted to assess the human PK of GSK3191607 following intravenous administration of [14C]-GSK3191607. METHODS: A human microdose study was conducted to investigate the clinical PK of GSK3191607 and enable a Go/No Go decision on further progression of the compound. The PK disposition parameters estimated from the microdose study, combined with preclinical in vitro and in vivo pharmacodynamic parameters, were all used to estimate the potential efficacy of various oral dosing regimens in humans. RESULTS: The PK profile, based on the microdose data, demonstrated a half-life (~17 h) similar to other antimalarial compounds currently in clinical development. However, combining the microdose data with the pharmacodynamic data provided results that do not support further clinical development of the compound for a single dose cure. CONCLUSIONS: The information generated by this study provides a basis for predicting the expected oral PK profiles of GSK3191607 in man and supports decisions on the future clinical development of the compound.


Assuntos
Antimaláricos/administração & dosagem , Plasmodium falciparum/efeitos dos fármacos , Administração Intravenosa , Adulto , Antimaláricos/farmacocinética , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Especificidade da Espécie
8.
Nat Commun ; 8(1): 430, 2017 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-28874661

RESUMO

To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC50 of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC50 of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a P. falciparum SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature P. falciparum gametocytes to Anopheles stephensi mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug.Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Imidazóis/uso terapêutico , Malária/enzimologia , Malária/transmissão , Piridinas/uso terapêutico , Animais , Linhagem Celular , Cristalografia por Raios X , Culicidae , Proteínas Quinases Dependentes de GMP Cíclico/química , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Imidazóis/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária/tratamento farmacológico , Camundongos Endogâmicos BALB C , Modelos Moleculares , Plasmodium chabaudi/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia , Resultado do Tratamento
9.
Int. j. morphol ; 35(3): 1037-1042, Sept. 2017. ilus
Artigo em Inglês | LILACS | ID: biblio-893090

RESUMO

This study will examine how differences in measurements between bizygomatic and bigonial arches of the human face can provide relevant information regarding personality and abilities of the subject. Sample: 82 males. Group A: 55 subjects with the bizygomatic arch in contraction. Group B: 27 subjects without the bizygomatic arch in contraction. Subjects performed self-assessment tests in the following areas: ability incorporating themselves into the group, alexithymia and emotional expressiveness. Group A showed greater self-sufficiency and independence than group B, greater difficulty in describing and verbally expressing their emotions, less ability to express themselves emotionally through other forms of communication and reduced willingness to cooperate philanthropically. Results suggest a strong relationship between morphological structure of the bizygomatic arch and certain psychological characteristics.


Este estudio examina cómo la diferencia entre las anchuras del arco bicigomático y bigonial en la cara humana, proporcionan información relevante sobre la personalidad y las habilidades de un sujeto. Muestra: 82 hombres. Grupo A: 55 sujetos con el arco bicigomático en contracción. Grupo B: 27 sujetos con el arco bicigomático sin retracción. Los sujetos realizaron pruebas de autoevaluación en las siguientes áreas: adhesión/independencia al grupo, alexitimia y expresividad emocional. El grupo A mostró respecto al grupo B una mayor autosuficiencia e independencia, mayor dificultad para describir y expresar verbalmente sus emociones, menor capacidad para expresarse emocionalmente a través de diferentes formas de comunicación y reducción de la voluntad de cooperar filantrópicamente. Los resultados sugieren una fuerte relación entre la estructura morfológica del arco bicigomático y ciertas características psicológicas.


Assuntos
Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Sintomas Afetivos , Cefalometria/métodos , Personalidade , Zigoma/anatomia & histologia
10.
Sci Transl Med ; 9(387)2017 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-28446690

RESUMO

As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment.


Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Aminopiridinas/uso terapêutico , Antimaláricos/uso terapêutico , Sulfonas/uso terapêutico , Aminopiridinas/farmacologia , Animais , Antimaláricos/farmacologia , Feminino , Malária/tratamento farmacológico , Malária/enzimologia , Masculino , Camundongos , Camundongos SCID , Testes de Sensibilidade Parasitária , Plasmodium/efeitos dos fármacos , Plasmodium/patogenicidade , Sulfonas/farmacologia
11.
J Pharmacokinet Pharmacodyn ; 44(2): 133-141, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28205025

RESUMO

The Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin on Mycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected with M. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day). Twenty-five mice received oral rifampicin (1, 3, 9, 26 or 98 mg·kg-1·day-1; Days 1-8; 5 each dose level) and were sacrificed on Day 9. Twenty mice received oral rifampicin (30 mg·kg-1·day-1; up to 8 days) and were sacrificed on Days 2, 3, 4 and 9 (5 each day). The MTP model was linked to a rifampicin population pharmacokinetic model to describe the change in colony forming units (CFU) in the lungs over time. The transfer rates between the different bacterial states were fixed to estimates from in vitro data. The MTP model described well the change in CFU over time after different exposure levels of rifampicin in an acute tuberculosis mouse model. Rifampicin significantly inhibited the growth of fast-multiplying bacteria and stimulated the death of fast- and slow-multiplying bacteria. The data did not support an effect of rifampicin on non-multiplying bacteria possibly due to the short duration of the study. The pharmacometric modelling framework using the MTP model can be used to perform investigations and predictions of the efficacy of anti-tubercular drugs against different bacterial states.


Assuntos
Antibióticos Antituberculose/farmacologia , Antibióticos Antituberculose/farmacocinética , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Rifampina/farmacocinética , Tuberculose/tratamento farmacológico , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL
12.
J Med Chem ; 59(21): 9890-9905, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27748596

RESUMO

Introduction of water-solubilizing groups on the 5-phenyl ring of a 2-aminopyrazine series led to the identification of highly potent compounds against the blood life-cycle stage of the human malaria parasite Plasmodium falciparum. Several compounds displayed high in vivo efficacy in two different mouse models for malaria, P. berghei-infected mice and P. falciparum-infected NOD-scid IL-2Rγnull mice. One of the frontrunners, compound 3, was identified to also have good pharmacokinetics and additionally very potent activity against the liver and gametocyte parasite life-cycle stages.


Assuntos
Antimaláricos/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária/tratamento farmacológico , Doenças Parasitárias em Animais/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Pirazinas/farmacologia , Animais , Antimaláricos/química , Antimaláricos/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Células Hep G2 , Humanos , Camundongos , Camundongos SCID , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Doenças Parasitárias em Animais/parasitologia , Testes de Sensibilidade Parasitária , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium falciparum/crescimento & desenvolvimento , Pirazinas/química , Pirazinas/metabolismo , Solubilidade , Relação Estrutura-Atividade , Água/química
13.
PLoS Med ; 13(10): e1002138, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27701420

RESUMO

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study.


Assuntos
Acrilamidas/farmacologia , Antimaláricos/farmacologia , Piperazinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Acrilamidas/farmacocinética , Animais , Antimaláricos/farmacocinética , Artemisininas/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Testes de Sensibilidade Microbiana , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Piperazinas/farmacocinética , Plasmodium berghei/efeitos dos fármacos
14.
Eur J Pharm Sci ; 93: 319-33, 2016 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-27473307

RESUMO

The current first-line therapy for drug-susceptible tuberculosis consists of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB). In this study, we determined the population pharmacokinetics (PopPK) of RIF, INH, EMB and PZA using original experimental sampling designs for single-dose intravenous (IV) and single- and multiple-dose oral administration studies in the mouse model, and used these PopPK models to develop and evaluate new, more informative sampling designs with the aim of reducing the number of animals required for each drug. The RIF, INH, EMB and PZA blood concentrations after single oral and IV doses and multiple-dose oral administrations based on the original designs were used in the PopPK analysis using NONMEM software. The final PopPK models described the data well. Stochastic simulation and estimation were used to optimise the designs. The relative bias and relative imprecision of each pharmacokinetic parameter for each drug were derived and assessed to choose the final designs. The final single-dose IV and oral designs included up to eight samples per mouse with a total of 24 mice required for RIF and EMB and 33 mice for INH and PZA. In the new multiple-dose (zipper) oral designs, the mice were divided into two groups of three per dose, and four samples were taken from each mouse to cover all seven or eight sampling time points. The final number of mice required for the multiple-dose oral designs was 30 for RIF, INH and EMB, 36 for PZA. The number of mice required in the new designs for RIF, INH and EMB was decreased by up to 7-fold and the relative bias and relative imprecision in the parameter estimates were at least similar to those in the original designs.


Assuntos
Antibióticos Antituberculose/farmacocinética , Modelos Biológicos , Animais , Antibióticos Antituberculose/sangue , Modelos Animais de Doenças , Etambutol/sangue , Etambutol/farmacocinética , Isoniazida/sangue , Isoniazida/farmacocinética , Camundongos Endogâmicos C57BL , Pirazinamida/sangue , Pirazinamida/farmacocinética , Rifampina/sangue , Rifampina/farmacocinética , Tamanho da Amostra
15.
J Med Chem ; 59(13): 6101-20, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27314305

RESUMO

In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting.


Assuntos
Antimaláricos/química , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/uso terapêutico , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Humanos , Malária/parasitologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Camundongos SCID , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia
16.
Antimicrob Agents Chemother ; 60(6): 3669-75, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27044554

RESUMO

Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ(-/-) (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stage Plasmodium falciparum challenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n = 8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems. In vivo 50% inhibitory concentrations (IC50s) were estimated at 2.0 µg/ml and 1.8 µg/ml in the NSG and IBSM models, respectively, aligning with 1.8 µg/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations. (This trial was registered at the Australian New Zealand Clinical Trials Registry [http://anzctr.org.au] under registration number ACTRN12612000323820.).


Assuntos
Antimaláricos/farmacocinética , Malária Falciparum/tratamento farmacológico , Mefloquina/farmacocinética , Plasmodium falciparum/efeitos dos fármacos , Adulto , Animais , Antimaláricos/sangue , Antimaláricos/farmacologia , Estudos de Coortes , Modelos Animais de Doenças , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Feminino , Voluntários Saudáveis , Humanos , Concentração Inibidora 50 , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Masculino , Mefloquina/sangue , Mefloquina/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Plasmodium falciparum/crescimento & desenvolvimento
17.
J Med Chem ; 58(21): 8713-22, 2015 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-26502160

RESUMO

Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure-activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to the identification of potent pyrazolopyridines, which showed good in vivo efficacy and pharmacokinetics profiles. The lead compounds also proved to be very potent in the parasite liver and gametocyte stages, which makes them of high interest.


Assuntos
Antimaláricos/química , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Pirazóis/química , Pirazóis/uso terapêutico , Piridinas/química , Piridinas/uso terapêutico , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Fígado/parasitologia , Malária/parasitologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Camundongos , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade
18.
Antimicrob Agents Chemother ; 59(2): 950-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25421480

RESUMO

Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity, with 50% inhibitory concentrations (IC50s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory Plasmodium falciparum isolates. Activities against ex vivo clinical isolates of both P. falciparum and Plasmodium vivax were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of Plasmodium berghei and P. falciparum infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.


Assuntos
Antimaláricos/uso terapêutico , Azepinas/uso terapêutico , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Malária/tratamento farmacológico , Quinazolinas/uso terapêutico , Animais , Antimaláricos/química , Azepinas/química , Feminino , Células Hep G2 , Histona Metiltransferases , Humanos , Malária Falciparum/tratamento farmacológico , Camundongos , Camundongos SCID , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/patogenicidade , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , Quinazolinas/química
19.
Proc Natl Acad Sci U S A ; 111(50): E5455-62, 2014 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-25453091

RESUMO

Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na(+) levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na(+) homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.


Assuntos
Antimaláricos/farmacologia , ATPases Transportadoras de Cálcio/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Isoquinolinas/farmacologia , Malária/tratamento farmacológico , Modelos Moleculares , Plasmodium/efeitos dos fármacos , Antimaláricos/farmacocinética , ATPases Transportadoras de Cálcio/genética , Senescência Celular/efeitos dos fármacos , Descoberta de Drogas , Resistência a Medicamentos/genética , Eritrócitos/efeitos dos fármacos , Citometria de Fluxo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Ensaios de Triagem em Larga Escala , Isoquinolinas/farmacocinética , Estrutura Molecular
20.
Nat Commun ; 5: 5521, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25422853

RESUMO

The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.


Assuntos
Amidas/farmacologia , Antimaláricos/farmacologia , Benzimidazóis/farmacologia , Eritrócitos/parasitologia , Malária/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Pirazóis/farmacologia , Sódio/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Feminino , Homeostase/efeitos dos fármacos , Humanos , Masculino , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/genética , Plasmodium berghei/metabolismo , Plasmodium falciparum/enzimologia , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas de Protozoários
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