| 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
An X-ray crystal structure of one of our previously discovered RORgammat inverse agonists bound to the RORgammat ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORgammat binding, forming four hydrogen bonding and ionic interactions with RORgammat. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.
Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORgammat inverse agonists.,Lu Z, Duan JJ, Xiao H, Neels J, Wu DR, Weigelt CA, Sack JS, Khan J, Ruzanov M, An Y, Yarde M, Karmakar A, Vishwakrishnan S, Baratam V, Shankarappa H, Vanteru S, Babu V, Basha M, Kumar Gupta A, Kumaravel S, Mathur A, Zhao Q, Salter-Cid LM, Carter PH, Murali Dhar TG Bioorg Med Chem Lett. 2019 Jun 20. pii: S0960-894X(19)30416-0. doi:, 10.1016/j.bmcl.2019.06.036. PMID:31257087[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lu Z, Duan JJ, Xiao H, Neels J, Wu DR, Weigelt CA, Sack JS, Khan J, Ruzanov M, An Y, Yarde M, Karmakar A, Vishwakrishnan S, Baratam V, Shankarappa H, Vanteru S, Babu V, Basha M, Kumar Gupta A, Kumaravel S, Mathur A, Zhao Q, Salter-Cid LM, Carter PH, Murali Dhar TG. Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORgammat inverse agonists. Bioorg Med Chem Lett. 2019 Jun 20. pii: S0960-894X(19)30416-0. doi:, 10.1016/j.bmcl.2019.06.036. PMID:31257087 doi:http://dx.doi.org/10.1016/j.bmcl.2019.06.036
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