title: Identification of novel TACE inhibitors compatible with topical application.
abstract: 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.
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France. Electronic address: gilles.ouvry@galderma.com.
authors.forename: Gilles
authors.initials: G
authors.lastname: Ouvry
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Yaël
authors.initials: Y
authors.lastname: Berton
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Yushma
authors.initials: Y
authors.lastname: Bhurruth-Alcor
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Bonnary
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Bouix-Peter
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Bouquet
authors.affiliation: Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France.
authors.forename: Marilyne
authors.initials: M
authors.lastname: Bourotte
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chambon
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Comino
authors.affiliation: Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Deprez
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Duvert
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Duvert
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Feriel
authors.initials: F
authors.lastname: Hacini-Rachinel
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Harris
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Anne-Pascale
authors.initials: AP
authors.lastname: Luzy
authors.affiliation: Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Mathieu
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Millois
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pascau
authors.affiliation: Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France.
authors.forename: Artur
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Polge
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Reitz
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Reversé
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Rosignoli
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Taquet
authors.affiliation: Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
authors.forename: Laurent F
authors.initials: LF
authors.lastname: Hennequin
mesh_terms: D000072198:ADAM17 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000287:Administration, Topical; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000737:chemistry*; D011565:Psoriasis / Q000188:drug therapy / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D000072198:ADAM17 Protein
keywords: Enzyme-cell drop-off; Hydroxamic acids; Psoriasis; TACE; Topical application