Route scouting and optimization of a potent sulfoximine-based inverse agonist of RORγt

During our research looking for novel inverse agonists of RORγt, we identified a potent sulfoximine-based modulator as one of our pre-clinical candidates for the topical treatment for psoriasis. Herein, we describe the various routes we evaluated during the lead generation and optimization phases and the final route chosen for scale-up to deliver the first 100?g of API.     

Temperature-dependent interfacial properties of hydrophobically end-modified poly(2-isopropyl-2-oxazoline)s assemblies at the air/water interface and on solid substrates

We describe herein the properties at the air/water (A/W) interface of hydrophobically end-modified (HM) poly(2-isopropyl-2-oxazoline)s (PiPrOx) bearing an n-octadecyl chain on both termini (telechelic HM-PiPrOx) or on one chain end (semitelechelic HM-PiPrOx) for different subphase temperatures and spreading solvents using the Langmuir film balance technique. The polymer interfacial properties revealed by the π–A isotherms depend markedly on the architecture and molecular weight of the polymer. On cold water subphases (14 °C), diffusion of PiPrOx chains onto water takes place for all polymers in the intermediate compressibility region (5 mN m⁻¹). At higher subphase temperatures (36 and 48 °C), the HM-PiPrOx film exhibited remarkable stability with time. Brewster angle microscopy (BAM) imaging of the A/W interface showed that the polymer assembly was not uniform and that large domains formed, either isolated grains or pearl necklaces, depending on the polymer structure, the concentration of the spreading solution and the subphase temperature. The Langmuir films were transferred onto hydrophilic substrates (silica) by the Langmuir–Blodgett (LB) technique and onto hydrophobic substrates (gold) by Langmuir–Schaefer (LS) film deposition, resulting in the formation of adsorbed particles ranging in size from 200 to 500 nm, depending on the polymer architecture and the substrate temperature. The particles presented “Janus”-like hydrophilic/hydrophobic characteristics.     

Solution of near-field thermal radiation in one-dimensional layered media using dyadic Green's functions and the scattering matrix method

A general algorithm is introduced for the analysis of near-field radiative heat transfer in one-dimensional multi-layered structures. The method is based on the solution of dyadic Green's functions, where the amplitude of the fields in each layer is calculated via a scattering matrix approach. Several tests are presented where cubic boron nitride is used in the simulations. It is shown that a film emitter thicker than 1 μm provides the same spectral distribution of near-field radiative flux as obtained from a bulk emitter. Further simulations have pointed out that the presence of a body in close proximity to an emitter can alter the near-field spectrum emitted. This algorithm can be employed to study thermal one-dimensional layered media and photonic crystals in the near-field in order to design radiators optimizing the performances of nanoscale-gap thermophotovoltaic power generators.     

Weighing synthetic polymers of ultra‐high molar mass and polymeric nanomaterials: What can we learn from charge detection mass spectrometry?

Advances in soft ionization techniques for mass spectrometry (MS) of polymeric materials make it possible to determine the masses of intact molecular ions exceeding megadaltons. Interfacing MS with separation and fragmentation methods has additionally led to impressive advances in the ability to structurally characterize polymers. Even if the gap to the megadalton range has been bridged by MS for polymers standards, the MS‐based analysis for more complex polymeric materials is still challenging. Charge detection mass spectrometry (CDMS) is a single‐molecule method where the mass and the charge of each ion are directly determined from individual measurements. The entire molecular mass distribution of a polymer sample can be thus accurately measured. Described in this perspective paper is how molecular weight distribution as well as charge distribution can provide new insights into the structural and compositional studies of synthetic polymers and polymeric nanomaterials in the megadalton to gigadalton range of molecular weight. The recent multidimensional CDMS studies involving couplings with separation and dissociation techniques will be presented. And, finally, an outlook for the future avenues of the CDMS technique in the field of synthetic polymers of ultra‐high molar mass and polymeric nanomaterials will be provided.     

High‐order asymptotic‐preserving schemes for linear systems: Application to the Goldstein–Taylor equations

In this work, we address the numerical approximation of linear systems with possibly stiff source terms which induce an asymptotic diffusion limit. More precisely, we are interested in the design of high‐order asymptotic‐preserving schemes. Our approach is based on a very simple modification of the numerical flux associated with the usual HLL scheme. This alteration can be understood as a numerical diffusion reduction technique and allows to capture the correct asymptotic behavior in the diffusion limit and to consider uniformly high‐order extensions. We more specifically consider the case of the Goldstein–Taylor model but the overall approach is shown to be easily adapted to more general systems.     

Calcium and aluminum-based fillers as flame-retardant additives in silicone matrices. III. Investigations on fire reaction

The flame retardancy of silicone composites containing calcium- and aluminum-based fillers has been investigated using several methods including cone calorimeter, Pyrolysis Combustion Flow Calorimeter (PCFC), thermogravimetric analysis and pyrolysis-gas chromatography-mass spectrometry analysis (Py-GC/MS). The fire reaction of precipitated calcium carbonate, calcite, calcium hydroxide, aluminum trihydrate, boehmite and alumina-based composites was correlated mainly with their thermal stability, while for mica and wollastonite-based composites, a barrier effect was also evidenced. The endothermic effect was not established as an efficient flame retardancy mechanism for the silicone composites containing hydrated fillers. Mica composite exhibited the best flame retardancy, in terms of depressed HRR, among all investigated formulations. Finally, a unique behavior was observed during the cone calorimeter test of calcium hydroxide-based composite, which co-crystallization with silica occurs exclusively at high heat flux.     

Access to Heteroleptic Fluorido-Cyanido Complexes with a Large Magnetic Anisotropy by Fluoride Abstraction

Silicon-mediated fluoride abstraction is demonstrated as a means of generating the first fluorido-cyanido transition metal complexes. This new synthetic approach is exemplified by the synthesis and characterization of the heteroleptic complexes, trans-[M^IVF₄(CN)₂]²⁻ (M=Re, Os), obtained from their homoleptic [M^IVF₆]²⁻ parents. As shown by combined high-field electron paramagnetic resonance spectroscopy and magnetization measurements, the partial substitution of fluoride by cyanide ligands leads to a marked increase in the magnetic anisotropy of trans-[ReF₄(CN)₂]²⁻ as compared to [ReF₆]²⁻, reflecting the severe departure from an ideal octahedral (O_h point group) ligand field. This methodology paves the way toward the realization of new heteroleptic transition metal complexes that may be used as highly anisotropic building-blocks for the design of high-performance molecule-based magnetic materials.