Structure of Obeticholic Acid
CAS No.: 459789-99-2
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Obeticholic acid is a selective FXR agonist with EC50 of 99 nM and it has anticholestatic activity.
Synonyms: INT-747; 6-ECDCA; Ocaliva.
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Jaclynn A. Meshanni ; Jordan M. Lee ; Kinal N. Vayas ; Rachel Sun ; Chenghui Jiang ; Grace L. Guo , et al.
Abstract: Nitrogen mustard (NM) is a cytotoxic vesicant known to cause pulmonary injury that can progress to fibrosis. NM toxicity is associated with an influx of inflammatory macrophages in the lung. Farnesoid X receptor (FXR) is a nuclear receptor involved in bile acid and lipid homeostasis that has anti-inflammatory activity. In these studies, we analyzed the effects of FXR activation on lung injury, oxidative stress, and fibrosis induced by NM. Male Wistar rats were exposed to phosphate-buffered saline (vehicle control) or NM (0.125 mg/kg) by intratracheal Penncentury-MicroSprayer aerosolization; this was followed by treatment with the FXR synthetic agonist, obeticholic acid (OCA, 15 mg/kg), or vehicle control (0.13–0.18 g peanut butter) 2 hours later and then once per day, 5 days per week thereafter for 28 days. NM caused histopathological changes in the lung, including epithelial thickening, alveolar circularization, and pulmonary edema. Picrosirius red staining and lung hydroxyproline content were increased, indicative of fibrosis; foamy lipid-laden macrophages were also identified in the lung. This was associated with aberrations in pulmonary function, including increases in resistance and hysteresis. Following NM exposure, lung expression of HO-1 and iNOS, and the ratio of nitrates/nitrites in bronchoalveolar lavage fluid (BAL), markers of oxidative stress increased, along with BAL levels of inflammatory proteins, fibrinogen, and sRAGE. Administration of OCA attenuated NM-induced histopathology, oxidative stress, inflammation, and altered lung function. These findings demonstrate that FXR plays a role in limiting NM-induced lung injury and chronic disease, suggesting that activating FXR may represent an effective approach to limiting NM-induced toxicity.
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Identification of a novel mechanism driving NAFLD progression and therapeutic strategies
Myllys, Maiju ;
Abstract: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries with an increasing prevalence of approximately 25%. NAFLD comprises several stages, starting as benign steatosis and progressing to non-alcoholic steatohepatitis (NASH), and in some cases to liver cirrhosis and hepatocellular carcinoma (HCC). Although several emerging therapies are currently in clinical trials, so far there are no approved drugs for treatment of NASH. This is mainly because the driving mechanisms behind NAFLD progression are rather poorly understood. Consequently, NAFLD represents the second most common cause for liver transplantation. The overarching goal of this thesis was to investigate the mechanisms of NAFLD stage transitions, and to establish preventive measures for the progression from benign steatosis to NASH. For this purpose, a mouse model of NAFLD progression was first established by long-term feeding of male C57Bl/6N mice with western-style diet (WD) up to 54 weeks. The disease progression was evaluated time-dependently by biochemical, histopathological, and immunohistochemical analyses as well as by intravital two-photon-based imaging. This comprehensive analyses revealed six stages in NAFLD progression:(1) benign steatosis,(2) macrophage crown-like structure formation,(3) macropinocytosis of bile,(4) ductular reaction,(5) dedifferentiation and functional shutdown, and (6) tumor nodule formation. Particularly, the novel finding of this thesis was the identification of stage 3, macropinocytosis of bile, where a retrograde vesicular uptake of bile from bile canaliculi to hepatocytes led to toxic accumulation of bile acids in the liver tissue, providing a link between NAFLD and cholestasis. The phenomenon was further identified as macropinocytosis by treating the mice with a macropinocytosis-specific inhibitor imipramine. As a result, a single application of imipramine efficiently blocked macropinocytosis in WD-fed mice. Interestingly, a long-term application of imipramine for 8 weeks decreased the bile acid concentrations in the liver tissue and led to significant NAFLD amelioration. To study whether these findings are also relevant for human NAFLD, liver biopsies from patients at different stages of NAFLD were also analysed. Interestingly, bile macropinocytosis was also relevant in the NAFLD patients as detected by the presence of fragments of bile canaliculi within steatotic hepatocytes. In conclusion, an NAFLD mouse model recapitulating the different stages of human NAFLD progression to NASH and eventually to HCC was successfully established. Moreover, a novel mechanism possibly driving NALFD progression was identified as macropinocytosis of bile from bile canaliculi back to hepatocytes. Inhibition of macropinocytosis may represent an attractive therapeutic target to prevent NAFLD progression in human patients.
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CAS No. : | 459789-99-2 |
Formula : | C26H44O4 |
M.W : | 420.63 |
SMILES Code : | C[C@]12CC[C@H](C[C@@]1([H])[C@H]([C@H]([C@]([H])1[C@@]([H])3CC[C@@]([H])([C@]3(CC[C@@]12[H])C)[C@H](C)CCC(=O)O)O)CC)O |
Synonyms : |
INT-747; 6-ECDCA; Ocaliva.
|
MDL No. : | MFCD16621104 |
InChI Key : | ZXERDUOLZKYMJM-ZWECCWDJSA-N |
Pubchem ID : | 447715 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
In Vitro:
Concentration | Treated Time | Description | References |
Primary mouse hepatocytes | 1 μM | 24 h | To study the effect of FXR ligands on Ostβ expression, results showed that OCA induced Ostβ expression 181-fold in WT hepatocytes and 50% in hs-RxrαΔex4-/- hepatocytes. | PMC3946967 |
WB-F344 cells | 10 µM | 4 days | To evaluate the inhibitory effects of main constituents on ductular reaction in sodium butyrate-induced WB-F344 cell model. The results showed that these compounds (10 µM) and ASTs (10 μg/ml) significantly decreased the mRNA expression of CK19 in SB-induced WB-F344 cells. | PMC9632275 |
In Vivo:
Administration | Dosage | Frequency | Description | References |
mice | streptozotocin-induced NASH model | oral | 10 mg/kg | once daily for 4 weeks | OCA showed improvements in liver histopathology in the streptozotocin-induced NASH model but had no significant effect on improving cholesterol balance | PMC6939295 |
Mice | MCD diet-induced NASH model | Oral | 6.5 mg/kg | Once daily for 8 weeks | To evaluate the effects of Obeticholic Acid on serum lipids, bile acids, and gut microbiota in MCD diet-induced NASH mice. Results showed that Obeticholic Acid significantly reduced serum ALT, TG, and MDA levels and improved liver pathology. | PMC10587424 |
Mice | DDC-induced cholestatic liver disease model | Oral | 10 mg/kg | Once daily for 4 weeks | To evaluate the ameliorative effects of Obeticholic Acid in DDC-induced cholestatic liver disease model. The results showed that Obeticholic Acid significantly improved serum ALT, AST, TBiL, DBiL, and IBiL levels, but there was no significant difference in liver Hyp content and Sirius red positive area compared to the model group. | PMC9632275 |
Clinical Trial:
NCT Number | Conditions | Phases | Recruitment | Completion Date | Locations |
NCT02654236 | Alcohol Consumption | Not Applicable | Recruiting | July 2019 | United States, Indiana ... More >> Indiana University Recruiting Indianapolis, Indiana, United States, 46202 Contact: Jennifer Lehman, RN 317-278-1872 jgeck@iu.edu Contact: Megan Comerford, BS, MPH 3172789226 mcomerfo@iu.edu Sub-Investigator: Naga Chalasani, MD Principal Investigator: Suthat Liangpunsakul, MD Sub-Investigator: David Crabb, MD Less << |
NCT00501592 | Diabetes Mellitus, Type II ... More >> Fatty Liver Less << | Phase 2 | Completed | - | United States, California ... More >> Profil Institute for Clinical Research, Inc. Chula Vista, California, United States, 91911 UC San Diego VAMC San Diego, California, United States, 92161 United States, Texas Diabetes & Glandular Disease Research Associates, Inc. San Antonio, Texas, United States, 78229 United States, Virginia Virginia Commonwelath University Richmond, Virginia, United States, 23298 Less << |
NCT00570765 | Liver Cirrhosis, Biliary | Phase 2 | Completed | - | United States, Michigan ... More >> Henry Ford Novi, Michigan, United States, 39450 United States, Texas Baylor College of Medicine Houston, Texas, United States, 77030 United States, Virginia McGuire DVAMC Richmond, Virginia, United States, 23219 United States, Washington Virginia Mason Medical Center Seattle, Washington, United States, 98101 Austria Karls-Franzens University Graz, Austria, A8036 Canada, Alberta University of Alberta Edmonton, Alberta, Canada, T6G 2C8 Canada, Ontario University of Toronto Toronto, Ontario, Canada, M5T 2S8 Canada, Quebec Centre de Recherche du CHUM / University of Montreal Montreal, Quebec, Canada, H2X 1P1 France Hopital de l'Hotel Dieu Lyon, France, 69288 Hopital Saint-Antoine Paris, France, 75012 Germany Johann Wolfgang Goethe University Frankfurt, Germany, 60590 University Medical Centre Hamburg-Eppendorf Hamburg, Germany, D20246 Medical School of Hannover Hannover, Germany, 30623 University of Munich Munich, Germany, D81377 Spain Hospital Clinic i Provincial Barcelona, Spain, 08036 United Kingdom Queen Elizabeth Medical Center Edgbaston, Birmingham, United Kingdom, B15 2TH Royal Free Hospital Hampstead, London, United Kingdom, NW3 2QG John Radcliffe Hospital Headington, Oxford, United Kingdom, OX3 9DU Royal Infirmary Edinburgh, United Kingdom, EH16 4SA University Upon Tyne/Newcastle Newcastle Upon Tyne, United Kingdom, NE2 4HH Less << |
NCT00501592 | - | Completed | - | - | |
NCT00570765 | - | Completed | - | - | |
NCT03633227 | Liver Cirrhosis, Biliary | Phase 4 | Recruiting | June 1, 2020 | United States, California ... More >> Inland Empire Liver Foundation Recruiting Rialto, California, United States, 92377 Contact: Darlene Romo 909-883-2999 dromo@ieliverfoundation.com Contact: Nazly Amaya 909-883-2999 namaya@ieliverfoundation.com Principal Investigator: Zeid Kayali, MD United States, Texas American Research Corporation at Texas Liver Institute Recruiting San Antonio, Texas, United States, 78215 Contact: Nicole Forsyth 210-253-3426 nforsyth@txliver.com Contact: Elisha Moreno 210-253-3426 emoreno@txliver.com Principal Investigator: Eric Lawitz, MD Less << |
NCT01914562 | Healthy | Phase 1 | Completed | - | United States, Arizona ... More >> Celerion, Inc. Tempe, Arizona, United States, 85283 Less << |
NCT03703076 | - | Recruiting | April 2019 | France ... More >> Chu Grenoble Recruiting Grenoble, France, 38700 Contact: Vincent LEROY, MD 0476765450 ext +33 vleroy@chu-grenoble.fr Contact: Laure Bordy lbordy@chu-grenoble.fr Hopital Saint Antoine Recruiting Paris, France, 75571 Contact: Christophe Corpechot, MD 01 49 28 28 36 ext +33 christophe.corpechot@aphp.fr Less << | |
NCT00550862 | Liver Cirrhosis, Biliary | Phase 2 | Completed | - | - |
NCT00550862 | - | Completed | - | - | |
NCT01473524 | Primary Biliary Cirrhosis | Phase 3 | Active, not recruiting | June 2018 | - |
NCT02177136 | Primary Sclerosing Cholangitis... More >> (PSC) Less << | Phase 2 | Completed | - | - |
NCT01933503 | Healthy | Phase 1 | Completed | - | United States, Wisconsin ... More >> Spaulding Clinical Research West Bend, Wisconsin, United States, 53095 Less << |
NCT01904539 | Hepatic Impairment | Phase 1 | Completed | - | United States, Florida ... More >> Clinical Pharmacology of Miami, Inc. Miami, Florida, United States, 33014 Orlando Clinical Research Center Orlando, Florida, United States, 32809 Less << |
NCT03439254 | Compensated Cirrhosis ... More >> Nonalcoholic Steatohepatitis Less << | Phase 3 | Recruiting | July 2021 | - |
NCT03253276 | Primary Biliary Cirrhosis | Early Phase 1 | Recruiting | March 31, 2018 | Denmark ... More >> Susanne Keiding Recruiting Aarhus, Denmark, 8000 Contact: Susanne Keiding, prof +45 30939936 susakeid@rm.dk Contact: Michael Sørensen, PhD + 45 78463033 michsoer@rm.dk Less << |
NCT01865812 | Primary Biliary Cirrhosis | PHASE2 | COMPLETED | 2016-09-12 | Scripps Clinic, La Jolla, Cali... More >>fornia, 92037, United States|University of California, Davis Medical Center, Sacramento, California, 95817, United States|University of Miami, Miami, Florida, 33136, United States|Indiana University Medical Center, Indianapolis, Indiana, 46202, United States|Beth Israel Medical Center, New York, New York, 10003, United States|McGuire DVAMC, Richmond, Virginia, 23249, United States|Swedish Medical Center, Seattle, Washington, 98104, United States Less << |
NCT01625026 | Obesity Galls... More >>tones Less << | Phase 2 | Completed | - | Sweden ... More >> Hanns-Ulrich Marschall Göteborg, Sweden, 411 31 Less << |
NCT02177136 | - | Completed | - | - | |
NCT01265498 | Nonalcoholic Fatty Liver Disea... More >>se (NAFLD) Nonalcoholic Steatohepatitis (NASH) Less << | Phase 2 | Completed | - | United States, California ... More >> University of California, San Diego San Diego, California, United States, 92103 University of California, San Francisco San Francisco, California, United States, 94143 United States, Indiana Indiana University Indianapolis, Indiana, United States, 46202 United States, Missouri St. Louis University Saint Louis, Missouri, United States, 63104 United States, North Carolina Duke University Medical Center Durham, North Carolina, United States, 27710 United States, Ohio Case Western Reserve University Cleveland, Ohio, United States, 44109 Cleveland Clinic Foundation Cleveland, Ohio, United States, 44195 United States, Virginia Virginia Commonwealth University Richmond, Virginia, United States, 23298 United States, Washington Virginia Mason Medical Center Seattle, Washington, United States, 98101 Less << |
NCT01473524 | - | Active, not recruiting | - | - | |
NCT02308111 | Liver Cirrhosis, Biliary | Phase 4 | Recruiting | April 2025 | - |
NCT02532335 | Obesity | Phase 1 | Recruiting | October 2019 | Sweden ... More >> Hanns-Ulrich Marschall Recruiting Göteborg, Sweden, 411 31 Contact: Hanns-Ulrich Marschall +4670774073 hanns-ulrich.marschall@gu.se Principal Investigator: Hanns-Ulrich Marschall, MD, PhD Sahlgrenska Academy Enrolling by invitation Göteborg, Sweden Less << |
NCT02039219 | Alcoholic Hepatitis | Phase 2 | Completed | - | United States, Indiana ... More >> Indiana University Indianapolis, Indiana, United States, 46202 United States, Minnesota Mayo Clinic Rochester, Minnesota, United States, 55905 United States, Pennsylvania Einstein Healthcare Network Philadelphia, Pennsylvania, United States, 19141 United States, Virginia Virgina Commonwealth University Richmond, Virginia, United States, 23298 Less << |
NCT01265498 | - | Completed | - | - | |
NCT01865812 | Primary Biliary Cirrhosis | PHASE2 | COMPLETED | 2016-09-12 | Scripps Clinic, La Jolla, Cali... More >>fornia, 92037, United States|University of California, Davis Medical Center, Sacramento, California, 95817, United States|University of Miami, Miami, Florida, 33136, United States|Indiana University Medical Center, Indianapolis, Indiana, 46202, United States|Beth Israel Medical Center, New York, New York, 10003, United States|McGuire DVAMC, Richmond, Virginia, 23249, United States|Swedish Medical Center, Seattle, Washington, 98104, United States Less << |
NCT02430077 | Familial Partial Lipodystrophy | Phase 2 | Recruiting | December 2019 | United States, Texas ... More >> UT Southwestern Medical Center 5323 Harry Hines Blvd Recruiting Dallas, Texas, United States, 75390-8537 Contact: Claudia Quittner, RN claudia.quittner@utsouthwestern.edu Contact: Chandna Vasandani, Ph.D 214-648-5074 chandna.vasandani@utsouthwestern.edu Principal Investigator: Abhimanyu Garg, MD Sub-Investigator: Zahid Ahmad, M.D. UT Southwestern Medical Center 5323 Harry Hines Blvd Recruiting Dallas, Texas, United States, 75390-8537 Principal Investigator: Abhimanyu Garg, MD Sub-Investigator: Zahid Ahmad, M.D. UT Southwestern Medical Center Recruiting Dallas, Texas, United States, 75390 Contact: Claudia Quittner, RN 214-648-9296 claudia.quittner@utsouthwestern.edu Less << |
NCT02633956 | - | Completed | - | - | |
NCT01585025 | Primary Bile Acid Malabsorptio... More >>n Secondary Bile Acid Malabsorption Chronic Diarrhoea Less << | Phase 2 | Completed | - | United Kingdom ... More >> Hammersmith Hospital, Imperial College Healthcare NHS Trust London, United Kingdom, W12 0HS Hammersmith Hospital London, United Kingdom, W12 0HS Less << |
NCT02548351 | Non Alcoholic Steatohepatitis ... More >>(NASH) Less << | Phase 3 | Recruiting | October 2022 | - |
NCT02633956 | Nonalcoholic Steatohepatitis | Phase 2 | Completed | - | United States, Arizona ... More >> St. Joseph's Hospital and Medical Center Phoenix, Arizona, United States, 85013 United States, California Scripps Clinic La Jolla, California, United States, 92037 Inland Empire Liver Foundation Rialto, California, United States, 92377 United States, Florida Nature Coast Clinical Research Inverness, Florida, United States, 34452 University of Miamai, Schiff Center for Liver Diseases Miami, Florida, United States, 33136 South Florida Center of Gastroenterology Wellington, Florida, United States, 33414 Florida Medical Clinic, P.A. Zephyrhills, Florida, United States, 33542 United States, Hawaii The Queen's Medical Center - Liver Center Honolulu, Hawaii, United States, 96813 United States, Maryland Mercy Medical Center, Institute for Digestive Health & Liver Disease Baltimore, Maryland, United States, 21202 United States, Missouri Kansas City Research Institute Kansas City, Missouri, United States, 64131 St. Louis University Saint Louis, Missouri, United States, 63104 United States, North Carolina Duke University Medical Center Durham, North Carolina, United States, 27710 Cumberland Research Associates, LLC Fayetteville, North Carolina, United States, 28304 United States, Ohio Consultants for Clinical Research Cincinnati, Ohio, United States, 45249 United States, Pennsylvania Thomas Jefferson University Philadelphia, Pennsylvania, United States, 19107 United States, Rhode Island University Gastroenterology Liver Center Providence, Rhode Island, United States, 02905 United States, South Carolina Medical University of South Carolina Charleston, South Carolina, United States, 29425 United States, Tennessee ClinSearch Chattanooga, Tennessee, United States, 37421 United States, Texas Texas Clinical Research Institute, LLC Arlington, Texas, United States, 76012 Liver Associates of Texas, P.A. Houston, Texas, United States, 77030 American Research Corporation at the Texas Liver Institute San Antonio, Texas, United States, 78215 United States, Virginia McGuire DVAMC Richmond, Virginia, United States, 23249 Less << |
Bio Calculators | ||||
Preparing Stock Solutions | ![]() |
1mg | 5mg | 10mg |
1 mM 5 mM 10 mM |
2.38mL 0.48mL 0.24mL |
11.89mL 2.38mL 1.19mL |
23.77mL 4.75mL 2.38mL |