2. Academic Validation
  3. A Concise and Modular Approach to Generate Novel RORγ Agonists

A Concise and Modular Approach to Generate Novel RORγ Agonists

  • J Med Chem. 2025 Aug 14;68(15):15849-15871. doi: 10.1021/acs.jmedchem.5c00872.
Shunichi Fukuda 1 2,  Taku Ikenogami 1,  Kazuki Otake 1,  Shohei Miwa 1,  Katsuya Maeda 1,  Tomoya Yamashita 1,  Tasuku Inami 1,  Masahiro Yokota 1,  Yanhui Lu 1,  Akira Suma 1,  Yutaro Hirono 1,  Naoki Ogawa 1,  Teruhiko Inoue 1,  Kazuhito Harada 1,  Keishi Yamaguchi 1,  Shota Akai 1,  Akihiro Nomura 1,  Tsuyoshi Adachi 1,  Tsuyoshi Terawaki 1,  Akane Suzukawa 1,  Mari Kitamoto 1,  Minako Tanimoto 1,  Toru Noguchi 1,  Takahiro Hata 1,  Iichiro Kawahara 1,  Kazuhiko Iwamoto 1,  Kazuma Kondo 3,  Yoshihiro Kitagawa 1,  Yuichi Naka 1,  Paul Crowe 4,  Haiyan Tao 4,  Morgan Fenn 4,  Scott Thacher 4,  Makoto Oba 2,  Makoto Shiozaki 1
Affiliations

Affiliations

  • 1 Central Pharmaceutical Research Institute, Takatsuki Research Center, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • 2 Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo-hangi-cho, Sakyo-ku, Kyoto 603-0823, Japan.
  • 3 Central Pharmaceutical Research Institute, Yokohama Research Center, Japan Tobacco Inc., 1-13-2, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
  • 4 Orphagen Pharmaceuticals, 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States.
PMID: 40677142 DOI: 10.1021/acs.jmedchem.5c00872
Abstract

A variety of RORγ inhibitors have been identified, including clinical compounds such as VTP-43742 and JTE-151. In contrast, RORγ agonists have been less explored and LYC-55716 is, to the best of our knowledge, the sole example reached a human clinical investigation. To generate a novel RORγ Agonist, functionality switching from preceding RORγ inhibitors has been considered as a rational strategy. Such reported earlier attempts have been hampered by a loss of physicochemical properties to elevated lipophilicity. Starting from RORγ inhibitors, corresponding agonists were generated virtually to assess their druglike characters. Based on their ligand efficiency and lipophilicity, a cyclic amine carboxylate core was regarded as the best for maintaining favorable physicochemical properties. This scaffold was subjected to final optimization by attaching function-oriented modules retaining druglike properties. After multiparameter optimization, novel selective RORγ agonists were discovered, and their in vivo effects were confirmed in a syngeneic mouse model after oral administration.

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