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

[Display omitted] 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 pla...

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Published in:Bioorganic & medicinal chemistry 2018-02, Vol.26 (4), p.945-956
Main Authors: 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, Benoît, Duvert, Denis, Féret, Angélique, Hacini-Rachinel, Feriel, Harris, Craig S., 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 F.
Format: Article
Language:English
Subjects:
Aminonitrile synthesis
Life Sciences
Medication
Pharmaceutical sciences
Polymorph
Psoriasis
Solubility
TACE inhibitor
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Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2017.07.054