2. Academic Validation
  3. Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitor, S18-000003

Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitor, S18-000003

  • Bioorg Med Chem Lett. 2018 Dec 1;28(22):3549-3553. doi: 10.1016/j.bmcl.2018.09.032.
Yoshikazu Sasaki 1,  Masahide Odan 2,  Shiho Yamamoto 2,  Shiro Kida 2,  Azumi Ueyama 2,  Masaya Shimizu 2,  Takayo Haruna 2,  Ayahisa Watanabe 2,  Takayuki Okuno 2
Affiliations

Affiliations

  • 1 Pharmaceutical Research Division, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: yoshikazu.sasaki@shionogi.co.jp.
  • 2 Pharmaceutical Research Division, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
PMID: 30301676 DOI: 10.1016/j.bmcl.2018.09.032
Abstract

The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is the master transcription factor responsible for regulating the development and function of T-helper 17 (Th17) cells, which are related to the pathology of several autoimmune disorders. Therefore, RORγt is an attractive drug target for such Th17-mediated autoimmune diseases. A structure-activity relationship (SAR) study of lead compound 1 yielded a novel series of RORγt inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable RORγt inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration.

Keywords

Autoimmune disease; Cocrystal structure with ROR(γ)t LBD; IL-17; ROR(γ)t inhibitor; Th17 cell.

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