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Background: To support the rapid development of an antibody cocktail against Ebola virus and avoid unnecessary exposure to infectious environments, an automatic and fast turnover triplex assay was developed using Simoa ®  (Quanterix Corporation, MA, USA). Materials & methods: A robust triplex assay was developed and validated for simultaneous quantification of the antibody cocktail against Ebola virus in cynomolgus serum. Results: The assay had a quantitation range of 78.1-5000 ng/ml. The intra- and interassay precisions (%CV) were within 11.4 and 13.9%, and the accuracies (%RE) were within -10.8 to 6.8%, respectively. Cross-reactivity was evaluated, and the results met the acceptance criteria. Conclusion: The assay was successfully applied to a pharmacokinetics study following a single-dose intravenous administration of 10 mg/kg the antibody cocktail against Ebola virus to cynomolgus monkeys.

Recent years have seen a paradigm shift away from optimizing the brain:blood concentration ratio toward the more relevant brain:blood unbound concentration ratio (K p,uu,br ) in CNS drug discovery. Here, we review the recent developments in the in silico and in vitro model systems to predict the K p,uu,br of discovery compounds with special emphasis on the in-vitro – in-vivo correlation. We also discuss clinical ‘translation’ of rodent K p,uu,br and highlight the future directions for improvement in brain penetration prediction. Important in this regard are in silico K p,uu,br models built on larger datasets of high quality, calibration and deeper understanding of experimental in vitro transporter systems, and better understanding of blood–brain barrier transporters and their in vivo relevance aside from P-gp and BCRP. [ABSTRACT FROM AUTHOR]

Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson’s disease. Herein we disclose the discovery of a 4-ethoxy-7 H -pyrrolo[2,3- d ]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7 , which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100 mg/kg) and mice (45 mg/kg) following oral administration. [ABSTRACT FROM AUTHOR]

2-Aminopyrimidin-4(1 H )-one was proposed as the novel bioisostere of urea. Bioisosteric replacement of the reported urea series of the CXCR2 antagonists with 2-aminopyrimidin-4(1 H )-ones led to the discovery of the novel and potent CXCR2 antagonist 3e . 2-Aminopyrimidin-4(1 H )-one derivative 3e demonstrated a good developability profile (reasonable solubility and high permeability) and superior chemical stability especially in simulated gastric fluid (SGF) compared with ureas. [ABSTRACT FROM AUTHOR]