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
  • 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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