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 PubMedEmploying a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORgammat inverse agonists. Structure-activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORgammat inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis. Novel Tricyclic Pyroglutamide Derivatives as Potent RORgammat Inverse Agonists Identified using a Virtual Screening Approach.,Liu Q, Batt DG, Weigelt CA, Yip S, Wu DR, Ruzanov M, Sack JS, Wang J, Yarde M, Li S, Shuster DJ, Xie JH, Sherry T, Obermeier MT, Fura A, Stefanski K, Cornelius G, Khandelwal P, Tino JA, Macor JE, Salter-Cid L, Denton R, Zhao Q, Dhar TGM ACS Med Chem Lett. 2020 Nov 6;11(12):2510-2518. doi:, 10.1021/acsmedchemlett.0c00496. eCollection 2020 Dec 10. PMID:33335675[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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