Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors.

NLRP3 is a molecular sensor recognizing a wide range of danger signals. Its activation leads to the assembly of an inflammasome that allows for activation of caspase-1 and subsequent maturation of IL-1β and IL-18, as well as cleavage of Gasdermin-d and pyroptotic cell death. The NLRP3 inflammasome has been implicated in a plethora of diseases including gout, type 2 diabetes, atherosclerosis, Alzheimer's disease, and cancer.

Non-clinical characterization of the disposition of EMA401, a novel small molecule angiotensin II type 2 receptor (AT2R) antagonist.

EMA401, (the S-enantiomer of 5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), also known as Olodanrigan, is an orally active selective angiotensin II type 2 receptor (AT R) antagonist that is in Phase IIb clinical development as a novel analgesic for the relief of chronic pain. The main purpose of the present work was to investigate the disposition of a single C- labeled EMA401 in non-clinical studies. The in vitro metabolism studies of EMA401 were undertaken to understand the hepatic biotransformation pathways in animal species used in toxicology studies and how they compare to human.

Further Assessment of the Relay Hepatocyte Assay for Determination of Intrinsic Clearance of Slowly Metabolised Compounds Using Radioactivity Monitoring and LC-MS Methods.

Background And Objectives: Low-clearance drugs are widely used by industry mostly because of their often longer half-life, allowing for lower or less frequent dosing. Nevertheless, prediction of human clearance for these molecules from in vitro models presents a great challenge for pharmaceutical scientists. The objective of this study was to further characterise the predictive accuracy of the relay hepatocyte assay using C and H labelled proprietary compounds with a low extraction ratio and the known clearance mechanism in rats.

In Vitro Monitoring of the Mitochondrial Beta-Oxidation Flux of Palmitic Acid and Investigation of Its Pharmacological Alteration by Therapeutics.

Background And Objective: The present study was designed to validate the functional assay that enables rapid screening of therapeutic candidates for their effect on mitochondrial fatty acid oxidation.

Methods: The two whole-cell systems (tissue homogenates and hepatocytes) have been evaluated to monitor the total beta-oxidation flux of physiologically important H-palmitic acid by measurement of tritiated water enrichment in incubations using UPLC coupled on-line to radioactivity monitoring and mass spectrometry.

Results: Our results with several known inhibitors of fatty acid oxidation showed that this simple assay could correctly predict a potential in alteration of mitochondrial function by drug candidates.

Quantitative characterization of a polystyrene/poly(alpha-methylstyrene) blend by MALDI mass spectrometry and size-exclusion chromatography.

The use of coupled size-exclusion chromatography and MALDI mass spectrometry for quantitative measurement of the composition of technical polymer blends at the molecular level is described. The method is illustrated with a model binary blend consisting of polystyrene and poly(alpha-methylstyrene), both polymers having similar molecular weights and polydispersities. The proposed MALDI data treatment allows determination of the chemical composition of the blend, the molecular weights of the constituents, and the distributions of the homopolymers.

Polymer characterization by combining liquid chromatography with MALDI and ESI mass spectrometry.

High-performance polymers are complex mixtures of materials of different size and chemical composition and with different end groups and architecture. To determine the molecular heterogeneity of such systems, hyphenation of several techniques is required. The value of coupling mass spectrometry (MS) with separation techniques has already been recognized - such methods have proved to be among the most powerful for molecular characterization of complex polymer systems.