10 research outputs found
IMI – oral biopharmaceutics tools project – evaluation of bottom-up PBPK prediction success part 1: Characterisation of the OrBiTo database of compounds
The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to
The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria
The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to
The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria
Physiologically Based Pharmacokinetic Modeling for Sequential Metabolism: Effect of CYP2C19 Genetic Polymorphism on Clopidogrel and Clopidogrel Active Metabolite Pharmacokinetics
Improving Prediction of Metabolic Clearance Using Quantitative Extrapolation of Results Obtained From Human Hepatic Micropatterned Cocultures Model and by Considering the Impact of Albumin Binding
International audienc
Effects of Omeprazole and Genetic Polymorphism of CYP2C19 on the Clopidogrel Active Metabolite
Clopidogrel Pharmacodynamics and Pharmacokinetics in the Fed and Fasted State: A Randomized Crossover Study of Healthy Men
IMI – oral biopharmaceutics tools project – evaluation of bottom-up PBPK prediction success part 1: Characterisation of the OrBiTo database of compounds
The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance
The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria