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 nuclear receptor gamma t (RORgammat), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of RORgammat, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of RORgammat. The structure-activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent RORgammat inhibitory activity and a favorable pharmacokinetic profile.
Discovery of 6-Oxo-4-phenyl-hexanoic acid derivatives as RORgammat inverse agonists showing favorable ADME profile.,Nakajima R, Oono H, Kumazawa K, Ida T, Hirata J, White RD, Min X, Guzman-Perez A, Wang Z, Symons A, Singh SK, Mothe SR, Belyakov S, Chakrabarti A, Shuto S Bioorg Med Chem Lett. 2021 Mar 15;36:127786. doi: 10.1016/j.bmcl.2021.127786. , Epub 2021 Jan 23. PMID:33493627[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nakajima R, Oono H, Kumazawa K, Ida T, Hirata J, White RD, Min X, Guzman-Perez A, Wang Z, Symons A, Singh SK, Mothe SR, Belyakov S, Chakrabarti A, Shuto S. Discovery of 6-Oxo-4-phenyl-hexanoic acid derivatives as RORγt inverse agonists showing favorable ADME profile. Bioorg Med Chem Lett. 2021 Mar 15;36:127786. PMID:33493627 doi:10.1016/j.bmcl.2021.127786
