Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold
| Autor: | Akihiro Nomura, Kojo Arita, Paul D. Crowe, Kazuyuki Hirata, Makoto Shiozaki, Keisuke Ito, Naoki Miyagawa, Yoshiaki Katsuda, Kota Asahina, Hiromasa Hashimoto, Yoshihiro Suwa, Masayuki Kotoku, Haiyan Tao, Yasunori Hase, Yokota Masahiro, Seki Noriyoshi, Fujioka Shingo, Satoki Doi, Tsuyoshi Adachi, Masato Noguchi, Scott M. Thacher, Takayoshi Suzuki, Taku Ikenogami, Takaki Maeba |
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| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
Azoles Scaffold Drug discovery Dermatitis Computational biology Nuclear Receptor Subfamily 1 Group F Member 3 Scaffold hopping Molecular Docking Simulation Disease Models Animal Mice Structure-Activity Relationship chemistry In vivo Drug Discovery Molecular Medicine Potency Azole Structure–activity relationship Animals |
| Zdroj: | Journal of medicinal chemistry. 62(5) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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