RESUMO
Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.
Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/enzimologia , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Terapia de Alvo Molecular , Pirazóis/farmacologia , Pirimidinas/farmacologia , Animais , Quinase 9 Dependente de Ciclina/química , Quinases Ciclina-Dependentes/química , Quinases Ciclina-Dependentes/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Simulação de Acoplamento Molecular , Proteoma/efeitos dos fármacos , Proteômica , Pirazóis/química , Pirazóis/uso terapêutico , Pirimidinas/química , Pirimidinas/uso terapêutico , Reprodutibilidade dos Testes , Especificidade por SubstratoRESUMO
This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC0-τ) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged GSK3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA0-14) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at ClinicalTrials.gov under identifier NCT03075410.).
Assuntos
Antituberculosos/farmacologia , Compostos de Boro/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Tuberculose/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Antituberculosos/farmacocinética , Área Sob a Curva , Compostos de Boro/administração & dosagem , Compostos de Boro/efeitos adversos , Compostos de Boro/farmacocinética , Método Duplo-Cego , Inibidores Enzimáticos/farmacologia , Feminino , Alimentos , Compostos Heterocíclicos com 2 Anéis/administração & dosagem , Compostos Heterocíclicos com 2 Anéis/efeitos adversos , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Humanos , Leucina-tRNA Ligase/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Placebos , Adulto JovemRESUMO
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 EspécieRESUMO
The sensitivity of Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the activation process that transforms the prodrugs into their active antibacterial moieties. Various oxidases of M. tuberculosis have the potential to activate the prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic assay to select the N-acylated 4-phenylpiperidine compound series. The lead compound, SMARt751, interacted with the transcriptional regulator VirS of M. tuberculosis, which regulates the mymA operon encoding a monooxygenase that activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of ethionamide in mice infected with M. tuberculosis strains carrying mutations in the ethA gene, which cause ethionamide resistance in the clinic. SMARt751 was shown to be safe in tests conducted in vitro and in vivo. A model extrapolating animal pharmacokinetic and pharmacodynamic parameters to humans predicted that as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the dose of ethionamide administered while retaining the same efficacy and reducing side effects.
Assuntos
Mycobacterium tuberculosis , Pró-Fármacos , Tuberculose , Animais , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Etionamida/química , Etionamida/farmacologia , Etionamida/uso terapêutico , Camundongos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Tuberculose/tratamento farmacológicoRESUMO
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/toxicidadeRESUMO
N-tert-Butyl isoquine (4) (GSK369796) is a 4-aminoquinoline drug candidate selected and developed as part of a public-private partnership between academics at Liverpool, MMV, and GSK pharmaceuticals. This molecule was rationally designed based on chemical, toxicological, pharmacokinetic, and pharmacodynamic considerations and was selected based on excellent activity against Plasmodium falciparum in vitro and rodent malaria parasites in vivo. The optimized chemistry delivered this novel synthetic quinoline in a two-step procedure from cheap and readily available starting materials. The molecule has a full industry standard preclinical development program allowing first into humans to proceed. Employing chloroquine (1) and amodiaquine (2) as comparator molecules in the preclinical plan, the first preclinical dossier of pharmacokinetic, toxicity, and safety pharmacology has also been established for the 4-aminoquinoline antimalarial class. These studies have revealed preclinical liabilities that have never translated into the human experience. This has resulted in the availability of critical information to other drug development teams interested in developing antimalarials within this class.
Assuntos
Aminoquinolinas/farmacologia , Antimaláricos/farmacologia , Benzilaminas/farmacologia , Aminoquinolinas/síntese química , Aminoquinolinas/química , Aminoquinolinas/farmacocinética , Aminoquinolinas/toxicidade , Amodiaquina/análogos & derivados , Animais , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Antimaláricos/toxicidade , Benzilaminas/síntese química , Benzilaminas/química , Benzilaminas/toxicidade , Inibidores das Enzimas do Citocromo P-450 , Cães , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos , Feminino , Haplorrinos , Heme/química , Humanos , Malária/tratamento farmacológico , Camundongos , Modelos Moleculares , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium yoelii , Ratos , Relação Estrutura-AtividadeRESUMO
On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.