Discovery and process development of a novel TACE inhibitor for the topical treatment of psoriasis.

Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.

Identification of novel TACE inhibitors compatible with topical application.

Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.

Electrochemical imaging for microfluidics: a full-system approach.

Electrochemistry is developed as a new chemical imaging modality for microfluidics. The technique is based on multipoint voltammetry using an embedded 20 × 10 miniature electrode array implemented on a customized printed circuit board. Electrode durability was enhanced by chemical modification of the electrode surfaces, which enabled continuous, stable use for over 2 months. A system-level approach enables automatic calibration, data acquisition and data processing through a graphical user interface. Following data processing, redox currents and peak positions are extracted from location-specific voltammograms and converted into pixels of an "electrochemical image". The system is validated by imaging steady-state and dynamic laminar flow patterns of flow-confined solutions of the redox pairs Fe(CN)6(3-/4-) or multi-redox environments that include coflowing Ru(NH3)6(2+/3+) solutions. The images obtained are compared with flow simulations and optical images for validation. A strategy to achieve measurements with spatial resolution smaller than the individual electrodes is also demonstrated as an avenue to enhance image spatial resolution. It is expected that this new approach to chemical imaging will expand the applicability of microfluidics in certain areas of chemistry and biology without requiring expertise in electrochemistry.