| Structural highlights
Function
[NR1I2_HUMAN] Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORgammat inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at N1-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRalpha, and LXRbeta. Further optimization led to the discovery of (1R,4r)-4-((R)-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyr rolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.
Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active RORgammat Inverse Agonists.,Duan JJ, Lu Z, Jiang B, Stachura S, Weigelt CA, Sack JS, Khan J, Ruzanov M, Galella MA, Wu DR, Yarde M, Shen DR, Shuster DJ, Borowski V, Xie JH, Zhang L, Vanteru S, Gupta AK, Mathur A, Zhao Q, Foster W, Salter-Cid LM, Carter PH, Dhar TGM ACS Med Chem Lett. 2019 Feb 26;10(3):367-373. doi:, 10.1021/acsmedchemlett.9b00010. eCollection 2019 Mar 14. PMID:30891142[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest. 1998 Sep 1;102(5):1016-23. PMID:9727070 doi:10.1172/JCI3703
- ↑ Zhang J, Kuehl P, Green ED, Touchman JW, Watkins PB, Daly A, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Wrighton SA, Hancock M, Kim RB, Strom S, Thummel K, Russell CG, Hudson JR Jr, Schuetz EG, Boguski MS. The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics. 2001 Oct;11(7):555-72. PMID:11668216
- ↑ Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem. 2001 May 4;276(18):14581-7. Epub 2001 Jan 31. PMID:11297522 doi:10.1074/jbc.M010173200
- ↑ Li Y, Ross-Viola JS, Shay NF, Moore DD, Ricketts ML. Human CYP3A4 and murine Cyp3A11 are regulated by equol and genistein via the pregnane X receptor in a species-specific manner. J Nutr. 2009 May;139(5):898-904. doi: 10.3945/jn.108.103572. Epub 2009 Mar 18. PMID:19297428 doi:10.3945/jn.108.103572
- ↑ Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, Redinbo MR. 2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. Biochemistry. 2003 Feb 18;42(6):1430-8. PMID:12578355 doi:10.1021/bi0268753
- ↑ Teotico DG, Bischof JJ, Peng L, Kliewer SA, Redinbo MR. Structural basis of human pregnane X receptor activation by the hops constituent colupulone. Mol Pharmacol. 2008 Dec;74(6):1512-20. doi: 10.1124/mol.108.050732. Epub 2008 Sep, 2. PMID:18768384 doi:10.1124/mol.108.050732
- ↑ Duan JJ, Lu Z, Jiang B, Stachura S, Weigelt CA, Sack JS, Khan J, Ruzanov M, Galella MA, Wu DR, Yarde M, Shen DR, Shuster DJ, Borowski V, Xie JH, Zhang L, Vanteru S, Gupta AK, Mathur A, Zhao Q, Foster W, Salter-Cid LM, Carter PH, Dhar TGM. Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active RORgammat Inverse Agonists. ACS Med Chem Lett. 2019 Feb 26;10(3):367-373. doi:, 10.1021/acsmedchemlett.9b00010. eCollection 2019 Mar 14. PMID:30891142 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00010
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