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

Publication date: Available online 2 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Jean-Guy Boiteau, Gilles Ouvry, Jean-Marie Arlabosse, Stéphanie Astri, Audrey Beillard, Yushma Bhurruth-Alcor, Laetitia Bonnary, Claire Bouix-Peter, Karine Bouquet, Marilyne Bourotte, Isabelle Cardinaud, Catherine Comino, Benoît Deprez, Denis Duvert, Angélique Féret, Feriel Hacini-Rachinel, Craig S. Harris, Anne-Pascale Luzy, Arnaud Mathieu, Corinne Millois, Nicolas Orsini, Jonathan Pascau, Artur Pinto, David Piwnica, Gaëlle Polge, Arnaud Reitz, Kevin Reversé, Nicolas Rodeville, Patricia Rossio, Delphine Spiesse, Samuel Tabet, Nathalie Taquet, Loïc Tomas, Emmanuel Vial, Laurent F. Hennequin
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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