Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold

Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ inhibitor composed of a 4-(iso...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2019-03, Vol.62 (5), p.2837-2842
Main Authors: Kotoku, Masayuki, Maeba, Takaki, Fujioka, Shingo, Yokota, Masahiro, Seki, Noriyoshi, Ito, Keisuke, Suwa, Yoshihiro, Ikenogami, Taku, Hirata, Kazuyuki, Hase, Yasunori, Katsuda, Yoshiaki, Miyagawa, Naoki, Arita, Kojo, Asahina, Kota, Noguchi, Masato, Nomura, Akihiro, Doi, Satoki, Adachi, Tsuyoshi, Crowe, Paul, Tao, Haiyan, Thacher, Scott, Hashimoto, Hiromasa, Suzuki, Takayoshi, Shiozaki, Makoto
Format: Article
Language:English
Subjects:
Animals
Azoles - chemistry
Azoles - pharmacology
Dermatitis - drug therapy
Disease Models, Animal
Drug Discovery
Mice
Molecular Docking Simulation
Nuclear Receptor Subfamily 1, Group F, Member 3 - antagonists & inhibitors
Structure-Activity Relationship
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Summary:Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ inhibitor composed of a 4-(isoxazol-3-yl)­butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b01567