Tropifexor
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This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.
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Identification
- Generic Name
- Tropifexor
- DrugBank Accession Number
- DB16343
- Background
Tropifexor is under investigation in clinical trial NCT02516605 (A Multi-part, Double Blind Study to Assess Safety, Tolerability and Efficacy of Tropifexor (LJN452) in PBC Patients).
- Type
- Small Molecule
- Groups
- Investigational
- Structure
- Weight
- Average: 603.59
Monoisotopic: 603.145104743 - Chemical Formula
- C29H25F4N3O5S
- Synonyms
- Tropifexor
- External IDs
- LJN-452
- LJN452
- NVP-LJN452-NXA
Pharmacology
- Indication
Not Available
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- Pharmacodynamics
Not Available
- Mechanism of action
Target Actions Organism UBile acid receptor agonistbinderHumans - Absorption
Not Available
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
- Not Available
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Not Available
Categories
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- NMZ08KM76Z
- CAS number
- 1383816-29-2
- InChI Key
- VYLOOGHLKSNNEK-PIIMJCKOSA-N
- InChI
- InChI=1S/C29H25F4N3O5S/c30-21-9-15(27(37)38)10-23-25(21)34-28(42-23)36-16-7-8-17(36)12-18(11-16)39-13-20-24(35-41-26(20)14-5-6-14)19-3-1-2-4-22(19)40-29(31,32)33/h1-4,9-10,14,16-18H,5-8,11-13H2,(H,37,38)/t16-,17+,18+
- IUPAC Name
- 2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid
- SMILES
- OC(=O)C1=CC(F)=C2N=C(SC2=C1)N1[C@H]2CC[C@@H]1C[C@@H](C2)OCC1=C(ON=C1C1=C(OC(F)(F)F)C=CC=C1)C1CC1
References
- General References
- Not Available
- External Links
- ChemSpider
- 59718652
- BindingDB
- 50527040
- ChEMBL
- CHEMBL4298169
- PDBe Ligand
- GWF
- Wikipedia
- Tropifexor
- PDB Entries
- 7d42
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data2 Completed Treatment Non-Alcoholic Steatohepatitis (NASH) 1 somestatus stop reason just information to hide 2 Completed Treatment Primary Bile Acid Diarrhea 1 somestatus stop reason just information to hide 2 Completed Treatment Primary Biliary Cholangitis 1 somestatus stop reason just information to hide 2 Terminated Treatment Fatty Liver, Non-alcoholic Fatty Liver Disease, NAFLD / Steatohepatitis, Nonalcoholic 1 somestatus stop reason just information to hide 2 Terminated Treatment Non-Alcoholic Steatohepatitis (NASH) 2 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0129 mg/mL ALOGPS logP 5.36 ALOGPS logP 7.37 Chemaxon logS -4.7 ALOGPS pKa (Strongest Acidic) 3.58 Chemaxon pKa (Strongest Basic) 0.77 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 7 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 97.92 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 140.09 m3·mol-1 Chemaxon Polarizability 57.01 Å3 Chemaxon Number of Rings 7 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
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1. DetailsBile acid receptor
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- AgonistBinder
- General Function
- Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415). The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'-AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity (By similarity). In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis) (By similarity). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:12754200, PubMed:15471871, PubMed:17895379). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:10514450, PubMed:15239098, PubMed:16269519). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression (PubMed:12815072, PubMed:19085950). The function also involves the coordinated induction of hepatic KLB/beta-klotho expression (By similarity). Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA (PubMed:12806625, PubMed:16946559). Modulates lipid homeostasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly (PubMed:12554753, PubMed:12660231, PubMed:15337761). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance) (PubMed:11579204). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element (PubMed:11927623, PubMed:21804189). Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase) (PubMed:12891557). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3) (By similarity). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance (PubMed:20447400). Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier (By similarity). Down-regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells (PubMed:21242261). Mediates trans-repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2 (PubMed:19864602). Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays an anti-inflammatory role in liver inflammation; proposed to inhibit pro-inflammatory (but not antiapoptotic) NF-kappa-B signaling) (By similarity)
- Specific Function
- bile acid binding
- Gene Name
- NR1H4
- Uniprot ID
- Q96RI1
- Uniprot Name
- Bile acid receptor
- Molecular Weight
- 55913.915 Da
References
- Badman MK, Chen J, Desai S, Vaidya S, Neelakantham S, Zhang J, Gan L, Danis K, Laffitte B, Klickstein LB: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non-Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers. Clin Pharmacol Drug Dev. 2020 Apr;9(3):395-410. doi: 10.1002/cpdd.762. Epub 2019 Dec 10. [Article]
- Chianelli D, Rucker PV, Roland J, Tully DC, Nelson J, Liu X, Bursulaya B, Hernandez ED, Wu J, Prashad M, Schlama T, Liu Y, Chu A, Schmeits J, Huang DJ, Hill R, Bao D, Zoll J, Kim Y, Groessl T, McNamara P, Liu B, Richmond W, Sancho-Martinez I, Phimister A, Seidel HM, Badman MK, Joseph SB, Laffitte B, Molteni V: Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis. J Med Chem. 2020 Apr 23;63(8):3868-3880. doi: 10.1021/acs.jmedchem.9b01621. Epub 2020 Feb 5. [Article]
- Wang-Lakshman L, Miao Z, Wang L, Gu H, Kagan M, Gu J, McNamara E, Walles M, Woessner R, Camenisch G, Einolf HJ, Chen J: Evaluation of the Absorption, Metabolism, and Excretion of a Single Oral 1-mg Dose of Tropifexor in Healthy Male Subjects and the Concentration Dependence of Tropifexor Metabolism. Drug Metab Dispos. 2021 Jul;49(7):548-562. doi: 10.1124/dmd.120.000349. Epub 2021 May 5. [Article]
- Luo G, Lin X, Li Z, Xiao M, Li X, Zhang D, Xiang H: Structure-guided modification of isoxazole-type FXR agonists: Identification of a potent and orally bioavailable FXR modulator. Eur J Med Chem. 2021 Jan 1;209:112910. doi: 10.1016/j.ejmech.2020.112910. Epub 2020 Oct 7. [Article]
- Tully DC, Rucker PV, Chianelli D, Williams J, Vidal A, Alper PB, Mutnick D, Bursulaya B, Schmeits J, Wu X, Bao D, Zoll J, Kim Y, Groessl T, McNamara P, Seidel HM, Molteni V, Liu B, Phimister A, Joseph SB, Laffitte B: Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH). J Med Chem. 2017 Dec 28;60(24):9960-9973. doi: 10.1021/acs.jmedchem.7b00907. Epub 2017 Dec 8. [Article]
- Liu Y, Xiao Y, Chen S, Tian X, Wang W, Wang Y, Cai W: The Farnesoid X Receptor Agonist Tropifexor Prevents Liver Damage in Parenteral Nutrition-fed Neonatal Piglets. J Pediatr Gastroenterol Nutr. 2021 Jul 1;73(1):e11-e19. doi: 10.1097/MPG.0000000000003135. [Article]
- Jiang L, Xiao D, Li Y, Dai S, Qu L, Chen X, Guo M, Wei H, Chen Y: Structural basis of tropifexor as a potent and selective agonist of farnesoid X receptor. Biochem Biophys Res Commun. 2021 Jan 1;534:1047-1052. doi: 10.1016/j.bbrc.2020.10.039. Epub 2020 Oct 26. [Article]
- Hernandez ED, Zheng L, Kim Y, Fang B, Liu B, Valdez RA, Dietrich WF, Rucker PV, Chianelli D, Schmeits J, Bao D, Zoll J, Dubois C, Federe GC, Chen L, Joseph SB, Klickstein LB, Walker J, Molteni V, McNamara P, Meeusen S, Tully DC, Badman MK, Xu J, Laffitte B: Tropifexor-Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With the Antioxidative Gene Expression Profile in Rodents. Hepatol Commun. 2019 May 17;3(8):1085-1097. doi: 10.1002/hep4.1368. eCollection 2019 Aug. [Article]
- Xiao Y, Wang Y, Liu Y, Wang W, Tian X, Chen S, Lu Y, Du J, Cai W: A nonbile acid farnesoid X receptor agonist tropifexor potently inhibits cholestatic liver injury and fibrosis by modulating the gut-liver axis. Liver Int. 2021 Sep;41(9):2117-2131. doi: 10.1111/liv.14906. Epub 2021 May 18. [Article]
- Camilleri M, Nord SL, Burton D, Oduyebo I, Zhang Y, Chen J, Im K, Bhad P, Badman MK, Sanders DS, Walters JRF: Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea. Aliment Pharmacol Ther. 2020 Sep;52(5):808-820. doi: 10.1111/apt.15967. Epub 2020 Jul 23. [Article]
- Fiorucci S, Biagioli M, Baldoni M, Ricci P, Sepe V, Zampella A, Distrutti E: The identification of farnesoid X receptor modulators as treatment options for nonalcoholic fatty liver disease. Expert Opin Drug Discov. 2021 Oct;16(10):1193-1208. doi: 10.1080/17460441.2021.1916465. Epub 2021 May 5. [Article]
Drug created at December 15, 2020 20:02 / Updated at October 07, 2021 12:09