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.

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. ABSTRACT 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.)

AimsGSK3191607, 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.MethodsA 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.ResultsThe 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.ConclusionsThe 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.

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.

Resumen. Introduccion: Como parte del compromiso de GSK en la reduccion del fracaso en las fases de desarrollo clinico y preclinico, se ha implementado en las fases mas tempranas de desarrollo una estrategia para evitar los problemas de genotoxicidad que son los que, en mayor manera, pueden obstaculizar la progresion a fases mas avanzadas. El objetivo de este trabajo es aplicar la nueva estrategia de GSK para la priorizacion de compuestos que permita seleccionar aquellas estructuras con menor riesgo de genotoxicidad utilizando una combinacion de herramientas computacionales que predice el resultado del test de Ames. Materiales y Metodos: Compuestos de la coleccion de GSK, activos en el screening fenotipico frente a P. falciparum, fueron utilizados en este estudio. Tres modelos, Derek Nexus (Lhasa Limited, Leeds, UK , Leadscope y un metodo de ) mecanica cuantica desarrollado internamente se utilizaron para las predicciones in silico. Resultados: la combinacion de los tres modelos de prediccion tuvo un porcentaje de exito del 75% con solo 1 falso positivo. Conclusiones: Moleculas con 2 o mas alertas de genotoxicidad generadas por este sistema multiple deberian ser despriorizadas o ensayadas experimentalmente cuanto antes para descartar su riesgo de genotoxicidad. Palabras clave: In silico, antimalaricos, priorizacion, 3Rs, SAR

Associations between average total personal exposures to PM2.5, PM10, and NO2 and concomitant outdoor concentrations were assessed within the framework of the Genotox ER study. It was carried out in four French metropolitan areas (Grenoble, Paris, Rouen, and Strasbourg) with the participation, in each site, of 60–90 nonsmoking volunteers composed of two groups of equal size (adults and children) who carried the personal Harvard Chempass multipollutant sampler during 48 h along two different seasons ("hot" and "cold"). In each center, volunteers were selected so as to live (home and work/school) in three different urban sectors contrasted in terms of air pollution (one highly exposed to traffic emissions, one influenced by local industrial sources, and a background urban environment). In parallel to personal exposure measurements, a fixed ambient air monitoring station surveyed the same pollutants in each local sector. A linear regression model was accommodated where the dependent pollutant-specific variable was the difference, for each subject, between the average ambient air concentrations over 48 h and the personal exposure over the same period. The explanatory variables were the metropolitan areas, the three urban sectors, season, and age group. While average exposures to particles were underestimated by outdoor monitors, in almost all cities, seasons, and age groups, differences were lower for NO2 and, in general, in the other direction. Relationships between average total personal exposures and ambient air levels varied across metropolitan areas and local urban sectors. These results suggest that using ambient air concentrations to assess average exposure of populations, in epidemiological studies of long-term effects or in a risk assessment setting, calls for some caution. Comparison of personal exposures to PM or NO2 with ambient air levels is inherently disturbed by indoor sources and activities patterns. Discrepancies between measurement devices and local and regional sources of pollution may also strongly influence how the ambient air concentrations relate to population exposure. Much attention should be given to the selection of the most appropriate monitoring sites according to the study objectives.