| Literature DB >> 30301676 |
Yoshikazu Sasaki1, Masahide Odan2, Shiho Yamamoto2, Shiro Kida2, Azumi Ueyama2, Masaya Shimizu2, Takayo Haruna2, Ayahisa Watanabe2, Takayuki Okuno2.
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.Entities:
Keywords: Autoimmune disease; Cocrystal structure with ROR(γ)t LBD; IL-17; ROR(γ)t inhibitor; Th17 cell
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Year: 2018 PMID： 30301676 DOI： 10.1016/j.bmcl.2018.09.032
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823