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7087399 
Journal Article 
Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-gamma-t (ROR gamma t) inhibitor, S18-000003 
Sasaki, Y; Odan, M; Yamamoto, S; Kida, S; Ueyama, A; Shimizu, M; Haruna, T; Watanabe, A; Okuno, T; , 
2018 
Yes 
Bioorganic & Medicinal Chemistry Letters
ISSN: 0960-894X
EISSN: 1464-3405 
PERGAMON-ELSEVIER SCIENCE LTD 
OXFORD 
28 
22 
3549-3553 
English 
30301676 
WOS:000447747600011 
The retinoic acid receptor-related orphan receptor-gamma-t (ROR gamma t) 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, ROR(gamma)t 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 ROR(gamma)t inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable ROR(gamma)t inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration.