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

Autor: Boiteau JG; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France. Electronic address: jean-guy.boiteau@galderma.com., Ouvry G; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France. Electronic address: gilles.ouvry@galderma.com., Arlabosse JM; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Astri S; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Beillard A; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Bhurruth-Alcor Y; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Bonnary L; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Bouix-Peter C; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Bouquet K; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Bourotte M; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France., Cardinaud I; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Comino C; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Deprez B; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France., Duvert D; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Féret A; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Hacini-Rachinel F; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Harris CS; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Luzy AP; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Mathieu A; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France., Millois C; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Orsini N; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Pascau J; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Pinto A; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France., Piwnica D; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Polge G; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Reitz A; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Reversé K; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Rodeville N; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Rossio P; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Spiesse D; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Tabet S; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Taquet N; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Tomas L; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Vial E; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France., Hennequin LF; Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 Feb 15; Vol. 26 (4), pp. 945-956. Date of Electronic Publication: 2017 Aug 02.
DOI: 10.1016/j.bmc.2017.07.054
Abstrakt: 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.
(Copyright © 2017. Published by Elsevier Ltd.)
Databáze: MEDLINE
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