Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development

  • J Med Chem. 2024 Jan 25;67(2):952-970. doi: 10.1021/acs.jmedchem.3c01933.
Takaki Maeba  1  2 ,  Kazuyuki Hirata  1 ,  Masayuki Kotoku  3 ,  Noriyoshi Seki  1 ,  Katsuya Maeda  1 ,  Shintaro Hirashima  1 ,  Hiroshi Yamanaka  1 ,  Takayuki Sakai  1 ,  Shingo Obika  1 ,  Akimi Hori  1 ,  Yoshinori Hara  1 ,  Satoru Noji  1 ,  Yoshihiro Suwa  1 ,  Masahiro Yokota  1 ,  Shingo Fujioka  1 ,  Takayuki Yamaguchi  4 ,  Yoshiaki Katsuda  1 ,  Takahiro Hata  1 ,  Naoki Miyagawa  1 ,  Kojo Arita  4 ,  Yukihiro Nomura  1 ,  Toshio Taniguchi  1 ,  Kota Asahina  1 ,  Yusuke Aratsu  1 ,  Yuichi Naka  1 ,  Tsuyoshi Adachi  1 ,  Akihiro Nomura  1 ,  Shota Akai  1 ,  Shin-Ichi Oshida  5 ,  Sudhakar Pai  6 ,  Paul Crowe  7 ,  Erin Bradley  7 ,  Ruo Steensma  7 ,  Haiyan Tao  7 ,  Morgan Fenn  7 ,  Robert Babine  7 ,  Xiaolin Li  7 ,  Scott Thacher  7 ,  Takahiro Soeta  2 ,  Yutaka Ukaji  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. Division of Material Chemistry, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan.
  • 3. Akros Pharma Inc., Boston Office, One Broadway, 14th Floor, Cambridge, Massachusetts 02142, United States.
  • 4. Pharmaceutical Division, Japan Tobacco Inc., 3-4-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan.
  • 5. Central Pharmaceutical Research Institute, Yokohama Research Center, Japan Tobacco Inc., 1-13-2, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
  • 6. Akros Pharma Inc., 302 Carnegie Center, Suite 300, Princeton, New Jersey 08540, United States.
  • 7. Orphagen Pharmaceuticals, 11558 Sorrento Valley Road, Suite 4, San Diego, California 92121, United States.
PMID: 38170624 DOI: 10.1021/acs.jmedchem.3c01933
Abstract

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ Inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

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