Structural highlights
Function
[RORG_HUMAN] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.
Publication Abstract from PubMed
The retinoic acid receptor-related orphan receptor-gamma-t (RORgammat) 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, RORgammat 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 RORgammat inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable RORgammat inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration.
Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-gamma-t (RORgammat) inhibitor, S18-000003.,Sasaki Y, Odan M, Yamamoto S, Kida S, Ueyama A, Shimizu M, Haruna T, Watanabe A, Okuno T Bioorg Med Chem Lett. 2018 Dec 1;28(22):3549-3553. doi:, 10.1016/j.bmcl.2018.09.032. Epub 2018 Sep 27. PMID:30301676[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sasaki Y, Odan M, Yamamoto S, Kida S, Ueyama A, Shimizu M, Haruna T, Watanabe A, Okuno T. Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-gamma-t (RORgammat) inhibitor, S18-000003. Bioorg Med Chem Lett. 2018 Dec 1;28(22):3549-3553. doi:, 10.1016/j.bmcl.2018.09.032. Epub 2018 Sep 27. PMID:30301676 doi:http://dx.doi.org/10.1016/j.bmcl.2018.09.032
