Discovery of phenoxyindazoles and phenylthioindazoles as RORγ inverse agonists.
Targeting the IL17 pathway and more specifically the nuclear receptor RORγ is thought to be beneficial in multiple skin disorders. The Letter describes the discovery of phenoxyindazoles and thiophenoxy indazoles as potent RORγ inverse agonists. Optimization of the potency and efforts to mitigate the phototoxic liability of the series are presented. Finally, crystallization of the lead compound revealed that the series bound to an allosteric site of the nuclear receptor. Such compounds could be useful as tool compounds for understanding the impact of topical treatment on skin disease models.
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Gilles
G
Ouvry
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Claire
C
Bouix-Peter
NovAliX, Bld Sébastien Brant, Bioparc, 67405 Illkirch Cedex, France.
Fabrice
F
Ciesielski
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Laurent
L
Chantalat
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Olivier
O
Christin
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Catherine
C
Comino
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Denis
D
Duvert
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Christophe
C
Feret
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Craig S
CS
Harris
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Laurent
L
Lamy
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Anne-Pascale
AP
Luzy
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Branislav
B
Musicki
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Danielle
D
Orfila
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Jonathan
J
Pascau
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Véronique
V
Parnet
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Agnès
A
Perrin
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Romain
R
Pierre
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Gaëlle
G
Polge
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Catherine
C
Raffin
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Yves
Y
Rival
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Nathalie
N
Taquet
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Etienne
E
Thoreau
Galderma R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Laurent F
LF
Hennequin
D054314:Drug Inverse Agonism; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007191:Indazoles; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3
Allosteric; Inverse agonists; Phototoxicity; ROR gamma; Topical administration