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

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Boiteau, Jean-Guy | Ouvry, Gilles | Arlabosse, Jean-Marie | Astri, Stéphanie | Beillard, Audrey | Bhurruth-Alcor, Yushma | Bonnary, Laetitia | Bouix-Peter, Claire | Bouquet, Karine | Bourotte, Marilyne | Cardinaud, Isabelle | Comino, Catherine | Deprez, Benoit | Duvert, Denis | Féret, Angélique | Hacini-Rachinel, Feriel | Harris, Craig | Luzy, Anne-Pascale | Mathieu, Arnaud | Millois, Corinne | Orsini, Nicolas | Pascau, Jonathan | Pinto, Artur | Piwnica, David | Polge, Gaëlle | Reitz, Arnaud | Reversé, Kevin | Rodeville, Nicolas | Rossio, Patricia | Spiesse, Delphine | Tabet, Samuel | Taquet, Nathalie | Tomas, Loïc | Vial, Emmanuel | Hennequin, Laurent

Edité par CCSD ; Elsevier -

International audience. 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.

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