| 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
Structure-activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORgammat inverse agonist series represented by 1 with heterocyclic moieties led to the identification of three novel aza analogs 5-7. The hexahydropyrrolo[3,2-f]quinoline series 5 (X = N, Y = Z=CH) showed potency and metabolic stability comparable to series 1 but with improved in vitro membrane permeability and serum free fraction. This structural modification was applied to the hexahydrocyclopentanaphthalene series 3, culminating in the discovery of 8e as a potent and selective RORgammat inverse agonist with an excellent in vitro profile, good pharmacokinetic properties, and biologic-like in vivo efficacy in preclinical models of rheumatoid arthritis and psoriasis.
Azatricyclic Inverse Agonists of RORgammat That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis.,Liu Q, Xiao HY, Batt DG, Xiao Z, Zhu Y, Yang MG, Li N, Yip S, Li P, Sun D, Wu DR, Ruzanov M, Sack JS, Weigelt CA, Wang J, Li S, Shuster DJ, Xie JH, Song Y, Sherry T, Obermeier MT, Fura A, Stefanski K, Cornelius G, Chacko S, Khandelwal P, Dudhgaonkar S, Rudra A, Nagar J, Murali V, Govindarajan A, Denton R, Zhao Q, Meanwell NA, Borzilleri R, Dhar TGM ACS Med Chem Lett. 2021 Apr 30;12(5):827-835. doi:, 10.1021/acsmedchemlett.1c00112. eCollection 2021 May 13. PMID:34055233[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Liu Q, Xiao HY, Batt DG, Xiao Z, Zhu Y, Yang MG, Li N, Yip S, Li P, Sun D, Wu DR, Ruzanov M, Sack JS, Weigelt CA, Wang J, Li S, Shuster DJ, Xie JH, Song Y, Sherry T, Obermeier MT, Fura A, Stefanski K, Cornelius G, Chacko S, Khandelwal P, Dudhgaonkar S, Rudra A, Nagar J, Murali V, Govindarajan A, Denton R, Zhao Q, Meanwell NA, Borzilleri R, Dhar TGM. Azatricyclic Inverse Agonists of RORgammat That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis. ACS Med Chem Lett. 2021 Apr 30;12(5):827-835. doi:, 10.1021/acsmedchemlett.1c00112. eCollection 2021 May 13. PMID:34055233 doi:http://dx.doi.org/10.1021/acsmedchemlett.1c00112
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