| Structural highlights
6hty is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | DMS, GOL, GRH |
| Gene: | NCOA1, BHLHE74, SRC1 (HUMAN) |
| Activity: | Histone acetyltransferase, with EC number 2.3.1.48 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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
The P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types especially those involved in inflammatory and immune processes. High-throughput screening let to a new class of P2X4 inhibitors with substantial CYP 3A4 induction in human hepatocytes. A structure-guided optimization with respect to decreased PXR binding was started. It was found that the introduction of larger and more polar substituents on the ether linker led to less PXR binding while maintaining the P2X4 inhibitory potency. This translated into significantly reduced CYP-induction for compounds 71 and 73. Unfortunately, the in vivo PK profiles of these compounds were insufficient for the desired profile in humans. However, BAY-1797 (10) was identified and characterized as potent and selective P2X4 antagonist. This compound is suitable for in vivo studies in rodents, anti-inflammatory and anti-nociceptive effects of BAY-1797 were demonstrated in a mouse CFA inflammatory pain model.
Discovery and Characterization of the Potent and Selective P2X4 Inhibitor N-[4-(3-Chlorophenoxy)-3-sulfamoylphenyl]-2-phenylacetamide (BAY-1797) and Structure- guided Amelioration of its CYP3A4 Induction Profile.,Werner S, Mesch S, Hillig RC, Ter Laak AM, Klint J, Neagoe I, Laux-Biehlmann A, Dahllof H, Braeuer N, Puetter V, Nubbemeyer R, Schulz S, Bairlein M, Zollner TM, Steinmeyer A J Med Chem. 2019 Nov 20. doi: 10.1021/acs.jmedchem.9b01304. PMID:31746599[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
- ↑ Werner S, Mesch S, Hillig RC, Ter Laak AM, Klint J, Neagoe I, Laux-Biehlmann A, Dahllof H, Braeuer N, Puetter V, Nubbemeyer R, Schulz S, Bairlein M, Zollner TM, Steinmeyer A. Discovery and Characterization of the Potent and Selective P2X4 Inhibitor N-[4-(3-Chlorophenoxy)-3-sulfamoylphenyl]-2-phenylacetamide (BAY-1797) and Structure- guided Amelioration of its CYP3A4 Induction Profile. J Med Chem. 2019 Nov 20. doi: 10.1021/acs.jmedchem.9b01304. PMID:31746599 doi:https://dx.doi.org/10.1021/acs.jmedchem.9b01304
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