Discovery of an Oral, Rule of 5 Compliant, Interleukin 17A Protein-Protein Interaction Modulator for the Potential Treatment of Psoriasis and Other Inflammatory Diseases.

Interleukin 17A (IL-17A) is an interleukin cytokine whose dysregulation is implicated in autoimmune disorders such as psoriasis, and monoclonal antibodies against the IL-17A pathway are now well-established and very effective treatments. This article outlines the work that led to the identification of 23 as an oral, small-molecule protein-protein interaction modulator (PPIm) clinical development candidate. Protein crystallography provided knowledge of the key binding interactions between small-molecule ligands and the IL-17A dimer, and this helped in the multiparameter optimization toward identifying an orally bioavailable, Rule of 5 compliant PPIm of IL-17A. Overlap of early ligands led to a series of benzhydrylglycine-containing compounds that allowed the identification of dimethylpyrazole as a key substituent that gave PPIm with oral bioavailability. Exploration of the amino acid portion of the structure then led to dicyclopropylalanine as a group that gave potent and metabolically stable compounds, including the development candidate 23.

Quantitative determination of the anti-tumor agent tasquinimod in human urine by liquid chromatography-tandem mass spectrometry.

Tasquinimod is an anti-tumor drug that is currently in clinical development for the treatment of solid cancers. After oral administration, tasquinimod and a number of its metabolites are excreted in the urine. The quantitative determination of tasquinimod in urine is challenging because of the required sensitivity (down to 0.1nM or 40pg/mL), the highly variable nature of this biological matrix and the presence of potentially unstable metabolites, which may convert back to the parent drug. In this article, an LC-MS/MS method is described for the determination of tasquinimod in human urine in the concentration range 0.1-200nM. Liquid-liquid extraction with n-chlorobutane was used to extract tasquinimod from 100µL human urine and to remove interfering endogenous urinary constituents. Reversed-phase liquid chromatography coupled to a triple quadrupole mass spectrometer equipped with an ESI source was used for quantification of tasquinimod in a 2.5-min run. A stable-isotope labeled internal standard was used for response normalization. The intra- and inter-day coefficients of variation (precision) as well as the bias (accuracy) of the method were below 7%. Although considerable conversion of conjugated tasquinimod metabolites back to parent drug was observed when incurred samples were stored at 37°C for a prolonged time, tasquinimod as well as its metabolites were sufficiently stable under all relevant sampling, storage and analysis conditions. The method was successfully applied to determine the urinary excretion of tasquinimod in healthy volunteers and patients with renal impairment after a 0.5-mg oral dose.

A survey of airborne isocyanate exposure in 13 Swedish polyurethane industries.

Exposure to isocyanates can be harmful to workers by causing different disorders of the airways. The main objectives of this study were to survey the personal 8 h time-weighted average exposure to isocyanates at 13 Swedish plants that handled either polyurethane, diisocyanates or both, including four types of manufacturing processes: moulding, continuous foaming, flame lamination and low or no heating processes. A total of 223 air samples were collected for 111 workers with personal air monitoring using a dry filter method with 1-(2-methoxyphenyl)piperazine (2MP) as derivatization reagent. A further 272 stationary samples were collected, using the 2MP method, a modified 2MP method and an impinger method using dibutylamine in toluene. With the applied strategy, a large number of workers were monitored and four industrial environments were compared regarding the isocyanate exposure. All workers were found to be exposed to isocyanates in the range 0.004-5.2 p.p.b. On average, the personal exposure levels in the different types of manufacturing processes were, in decreasing order: continuous foaming > flame lamination > moulding >> low or no heating processes. However, there were variations in exposure levels in plants with similar processes and also between different shifts performing the same tasks. Isocyanic acid, which could not be sampled by the 2MP method used for personal monitoring, was found by short-term stationary monitoring in levels up to 38 p.p.b. in the flame lamination plants.

Determination of isocyanates in air using 1-(2-methoxyphenyl)piperazine-impregnated filters: long-term sampling performance and field comparison with impingers with dibutylamine.

Isocyanates may be harmful to workers and methods for monitoring air exposure in the field are necessary. The main aim of this study was to study the field performance of a method using 1-(2-methoxyphenyl)piperazine (2MP)-impregnated filters, by side-by-side comparison of long-term sampling with consecutive short-term samplings and also by short-term comparisons with other methods. Apart from using 2MP-impregnated filters, air monitoring was also performed by a modified 2MP method (FINMP) and by an impinger method using dibutylamine (DBA), which was the reference method. For short-term sampling the compared methods performed equally well for 2,6-toluenediisocyanate (2,6-TDI) and for isocyanic acid. For 2,4-toluenediisocyanate (2,4-TDI), the DBA method gave approximately 10% higher results according to linear regression than the 2MP method and for phenyl isocyanate, the DBA method gave significantly higher results than both the 2MP and FINMP methods. During long-term sampling (2-4 h) of TDI with the 2MP method, significantly lower levels were found compared with parallel sampling with consecutive short-term samplings. A time-dependent correction factor for long-term sampling was calculated to be 1.7 for 2,4-TDI and 1.5 for 2,6-TDI for 4 h sampling. The long-term sampling performance for other isocyanates was not studied. In conclusion, short-term monitoring shows that the 2MP method slightly underestimates the true air concentration for some of the isocyanates studied, but the error is relatively small considering the variation in exposure. For long-term monitoring the 2MP method can be applied for TDI but, since the method underestimates the concentrations, a correction factor is needed which needs to be corroborated further.