Article
Chemistry, Medicinal
Joseph Carpenter, Gang Wu, Ying Wang, Erica M. Cook, Tao Wang, Doree Sitkoff, Karen A. Rossi, Kathy Mosure, Xiaoliang Zhuo, Gary G. Cao, Milinda Ziegler, Anthony Azzara, Jack Krupinski, Matthew G. Soars, Bruce Alan Ellsworth, Dean A. Wacker
Summary: Compound 1 is a nonbile acid FXR agonist with potent activity, suitable ADME profile, and demonstrated efficacy in a mouse model, supporting further evaluation.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Moritz Helmstaedter, Jan Vietor, Jana Sommer, Simone Schierle, Sabine Willems, Astrid Kaiser, Jurema Schmidt, Daniel Merk
Summary: A new FXR modulator chemotype has been discovered with tunable activity between agonism and antagonism through minor structural modifications, showing high selectivity and binding affinities. This new FXR ligand compound demonstrates good metabolic stability in cells and can serve as a novel scaffold for FXR-targeted drug discovery.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Martha D. Gay, Hong Cao, Narayan Shivapurkar, Sivanesan Dakshanamurthy, Bhaskar Kallakury, Robin D. Tucker, John Kwagyan, Jill P. Smith
Summary: Nonalcoholic steatohepatitis (NASH) is linked to obesity, metabolic syndrome, and dysbiosis of the gut microbiome. This study showed that the CCK receptor inhibitor proglumide can improve NASH in a mouse model by interacting with FXR and altering the gut microbiome.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Chenlu Zhang, Yameng Liu, Ying Wang, Xie Ge, Tingying Jiao, Jianpeng Yin, Kanglong Wang, Cuina Li, Shimeng Guo, Xin Xie, Cen Xie, Fajun Nan
Summary: The intestinal FXR antagonist F6 showed significant anti-inflammatory and anti-fibrotic effects in NASH models and achieved its beneficial effects through direct antagonism of intestinal FXR and feedback activation of hepatic FXR.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Food Science & Technology
Fei Xiong, Zhongdaixi Zheng, Lingyu Xiao, Chuhong Su, Junbin Chen, Xiangfu Gu, Jiaqi Tang, Yue Zhao, Huiyu Luo, Longying Zha
Summary: The study found that SS-A(2) can significantly alleviate steatohepatitis in NASH mice by regulating BAs and gut microbiota, including reducing hepatic pathology, lowering NAS scores, and fibrosis.
MOLECULAR NUTRITION & FOOD RESEARCH
(2021)
Article
Gastroenterology & Hepatology
Stefania Grimaudo, Paola Dongiovanni, Jussi Pihlajamaki, Mohammed Eslam, Hannele Yki-Jarvinen, Rosaria Maria Pipitone, Guido Baselli, Calogero Camma, Vito Di Marco, Marco Enea, Miriam Longo, Grazia Pennisi, Daniele Prati, Rossella Zito, Anna Ludovica Fracanzani, Antonio Craxi, Jacob George, Stefano Romeo, Luca Valenti, Salvatore Petta
Summary: The NR1H4 gene rs35724 C allele is protective against severity of steatosis, steatohepatitis, and liver fibrosis, but is associated with higher total circulating cholesterol levels. Patients carrying the NR1H4 rs35724 C allele show increased hepatic mRNA levels of FXR and genes involved in bile acid synthesis. This suggests that increased hepatic FXR expression due to the NR1H4 rs35724 C allele may have potential therapeutic implications for NAFLD.
LIVER INTERNATIONAL
(2021)
Review
Biochemistry & Molecular Biology
Jing Zeng, Jiangao Fan, Huiping Zhou
Summary: Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), gradually progress to liver fibrosis, cirrhosis, and failure. Disruption of bile acid metabolism and intrahepatic circulation plays a crucial role in accelerating the progression of cholestatic liver diseases. Bile acids not only act as detergents for nutrition absorption but also function as key signaling molecules that regulate hepatic metabolism and immune responses. This review focuses on the role of bile acid-mediated signaling in cholestatic liver disease.
CELL AND BIOSCIENCE
(2023)
Article
Chemistry, Medicinal
Liang Dai, Qian Wang, Pengfei Wang, Shangran Zhang, Luyang Tai, Xiangrui Xu, Gang Sun, Mengyu Duan, Haoliang Yuan, Zhiqi Feng
Summary: Nonalcoholic steatohepatitis (NASH) is a growing public health burden with no effective therapeutic drugs. Sustained hepatic inflammation is the key histopathological feature of NASH. Researchers have discovered that the novel AdipoRon analogue Q7 exhibits potent anti-inflammatory activity and low cytotoxicity. In animal experiments, Q7 demonstrated superior anti-inflammatory, anti-fibrotic, and lipid-lowering effects compared to AdipoRon. Q7 shows promise as a potential anti-inflammatory and anti-NASH agent.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Xiangbing Shu, Meng Li, Ying Cao, Chunlin Li, Wenjun Zhou, Guang Ji, Li Zhang
Summary: The study demonstrates that berberine alleviates NASH by modulating the interplay of gut microbiota and bile acid metabolism, as well as the subsequent intestinal FXR activation.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Gastroenterology & Hepatology
Claudia D. Fuchs, Natalie Sroda, Hubert Scharnagl, Ruchi Gupta, Wesley Minto, Tatjana Stojakovic, John T. Liles, Grant Budas, David Hollenback, Michael Trauner
Summary: This study demonstrates that cilofexor, a non-steroidal FXR agonist, improves cholestatic liver injury and hepatic fibrosis in the Mdr2-/-mouse model of sclerosing cholangitis. These findings suggest the potential therapeutic properties of cilofexor in cholestatic liver diseases, mediated by intestinal FXR-mediated gut-liver signaling.
Article
Chemistry, Medicinal
Tingjun Xu, Wenxing Gao, Lixin Zhu, Wanning Chen, Chaoqun Niu, Wenjing Yin, Liangxiao Ma, Xinyue Zhu, Yunchao Ling, Sheng Gao, Lei Liu, Na Jiao, Weiming Chen, Guoqing Zhang, Ruixin Zhu, Dingfeng Wu
Summary: NAFLDkb is a specialized knowledge base and platform for computer-aided drug design against nonalcoholic fatty liver disease (NAFLD). It provides associations of drug-related entities as individual knowledge graphs, using curated information from diverse source materials and public databases. Practical drug discovery tools, including chemical structure search, drug-likeness screening, knowledge-based repositioning, and research article annotation, are implemented in the web interface. Case studies demonstrate the clinical reliability and potential of NAFLDkb in identifying novel drug-disease associations and accelerating NAFLD drug development. NAFLDkb is freely accessible at https://www.biosino.org/nafldkb and regularly updated with the latest findings.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Pharmacology & Pharmacy
Lili Xi, Axi Shi, Tiantian Shen, Guoxu Wang, Yuhui Wei, Jingjing Guo
Summary: Cholestasis is a common clinical disease caused by a disruption in bile acids homeostasis, and the Farnesoid X receptor (FXR) plays a critical role in regulating this balance. This study aimed to identify potential FXR agonists for the treatment of cholestasis using a molecular docking-based virtual screening method. Six compounds were selected and evaluated, with licraside showing the most promising results. In vivo evaluation using an animal model confirmed that licraside reduced biliary and serum markers of cholestasis and had a therapeutic effect on liver injury. These findings highlight the potential of licraside as an FXR agonist for cholestasis treatment, and the study contributes valuable insights into the development of novel compounds from traditional Chinese medicine.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Albrecht Boehlig, Florian Gerhardt, David Petroff, Florian van Boemmel, Thomas Berg, Valentin Blank, Thomas Karlas, Johannes Wiegand
Summary: This study investigated the prevalence of pruritus in a real-life NAFLD cohort and found significant associations between pruritus and anxiety, depression, and diabetes mellitus. The findings suggest that pruritus should be considered in the treatment of NAFLD patients with FXR agonists.
Review
Biochemistry & Molecular Biology
Nahum Mendez-Sanchez, Carlos E. Coronel-Castillo, Ana L. Ordonez-Vazquez
Summary: Cholestasis is a condition characterized by decreased bile flow, affecting the intrahepatic and extrahepatic biliary tree. It can lead to complications such as cirrhosis, liver failure, malignancies, bone disease, and nutritional deficiencies. Understanding the treatment options for cholestatic liver diseases is important due to the impact on mortality and quality of life. This review provides a comprehensive overview of the pathophysiology of cholangiopathies and aims to guide clinicians in the safe and effective treatment based on current evidence.
Review
Pharmacology & Pharmacy
Haiyan Li, Ting Guan, Shi Qin, Qihao Xu, Lina Yin, Qingzhong Hu
Summary: Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are liver diseases caused by systemic metabolic dysfunction, affecting a significant portion of the global adult population and posing high risks of progression to serious liver conditions. Current drug discovery focuses on modifying metabolic processes and inhibiting inflammation and fibrosis, with potential in natural compounds that have not been fully explored. Compounds found in healthy food could be used as adjuvants to lifestyle changes, while natural products like alkaloids and sesquiterpenoids show promise for further development through structural modifications.
DRUG DISCOVERY TODAY
(2023)
Article
Pharmacology & Pharmacy
Kapil Gadkar, Daniela Bumbaca Yadav, Joy Yu Zuchero, Jessica A. Couch, Jitendra Kanodia, Margaret K. Kenrick, Jasvinder K. Atwal, Mark S. Dennis, Saileta Prabhu, Ryan J. Watts, Sean B. Joseph, Saroja Ramanujan
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
(2016)
Article
Multidisciplinary Sciences
Rongsheng E. Wang, Ying Wang, Yuhan Zhang, Chase Gabrelow, Yong Zhang, Victor Chi, Qiangwei Fu, Xiaozhou Luo, Danling Wang, Sean Joseph, Kristen Johnson, Arnab K. Chatterjee, Timothy M. Wright, Van T. B. Nguyen-Tran, John Teijaro, Argyrios N. Theofilopoulos, Peter G. Schultz, Feng Wang
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2016)
Article
Oncology
Danielle Mandikian, Nene Takahashi, Amy A. Lo, Ji Li, Jeffrey Eastham-Anderson, Dionysos Slaga, Jason Ho, Maria Hristopoulos, Robyn Clark, Klara Totpal, Kedan Lin, Sean B. Joseph, Mark S. Dennis, Saileta Prabhu, Teemu T. Junttila, C. Andrew Boswell
MOLECULAR CANCER THERAPEUTICS
(2018)
Article
Pharmacology & Pharmacy
Danielle Mandikian, Isabel Figueroa, Amy Oldendorp, Hanine Rafidi, Sheila Ulufatu, Michelle G. Schweiger, Jessica A. Couch, Noel Dybdal, Sean B. Joseph, Saileta Prabhu, Gregory Z. Ferl, C. Andrew Boswell
Article
Multidisciplinary Sciences
Jeff Janes, Megan E. Young, Emily Chen, Nicole H. Rogers, Sebastian Burgstaller-Muehlbacher, Laura D. Hughes, Melissa S. Love, Mitchell V. Hull, Kelli L. Kuhen, Ashley K. Woods, Sean B. Joseph, H. Michael Petrassi, Case W. McNamara, Matthew S. Tremblay, Andrew I. Su, Peter G. Schultz, Arnab K. Chatterjee
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2018)
Article
Cell Biology
Malina A. Bakowski, Roohollah Kazem Shiroodi, Renhe Liu, Jason Olejniczak, Baiyuan Yang, Kerstin Gagaring, Hui Guo, Pamela M. White, Laura Chappell, Alain Debec, Frederic Landmann, Bettina Dubben, Franziska Lenz, Dominique Struever, Alexandra Ehrens, Stefan J. Frohberger, Hanna Sjoberg, Nicolas Pionnier, Emma Murphy, John Archer, Andrew Steven, Valerine C. Chunda, Fanny F. Fombad, Patrick W. Chounna, Abdel J. Njouendou, Haelly M. Metuge, Bertrand L. Ndzeshang, Narcisse Gandjui, Desmond N. Akumtoh, Tayong D. B. Kwenti, Ashley K. Woods, Sean B. Joseph, Mitchell Hull, Wen Xiong, Kelli L. Kuhen, Mark J. Taylor, Samuel Wanji, Joseph D. Turner, Marc P. Huebner, Achim Hoerauf, Arnab K. Chatterjee, Jason Roland, Matt S. Tremblay, Peter G. Schultz, William Sullivan, Xin-Jie Chu, H. Michael Petrassi, Case W. McNamara
SCIENCE TRANSLATIONAL MEDICINE
(2019)
Article
Chemistry, Medicinal
Elsa Pflimlin, Sam Lear, Candy Lee, Shan Yu, Huafei Zou, Andrew To, Sean Joseph, Van Nguyen-Tran, Matthew S. Tremblay, Weijun Sheng
ACS MEDICINAL CHEMISTRY LETTERS
(2019)
Article
Multidisciplinary Sciences
Amin Ardestani, Sijia Li, Karthika Annamalai, Blaz Lupse, Shirin Gerayandi, Aleksandra Dobrowolski, Shan Yu, Siying Zhu, Tyler D. Baguley, Murali Surakattula, Janina Oetjen, Lena Hauberg-Lotte, Raquel Herranz, Sushil Awal, Delsi Altenhofen, Van Nguyen-Tran, Sean Joseph, Peter G. Schultz, Arnab K. Chatterjee, Nikki Rogers, Matthew S. Tremblay, Weijun Shen, Kathrin Maedler
NATURE COMMUNICATIONS
(2019)
Article
Chemistry, Medicinal
Elsa Pflimlin, Zhihong Zhou, Zaid Amso, Qiangwei Fu, Candy Lee, Avinash Muppiddi, Sean B. Joseph, Van Nguyen-Tran, Weijun Shen
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Donatella Chianelli, Paul Rucker, Jason Roland, David C. Tully, John Nelson, Xiaodong Liu, Badry Bursulaya, Eloy D. Hernandez, Jane Wu, Mahavir Prashad, Thierry Schlama, Yugang Liu, Alan Chu, James Schmeits, David J. Huang, Robert Hill, Dingjiu Bao, Jocelyn Zoll, Young Kim, Todd Groessl, Peter McNamara, Bo Liu, Wendy Richmond, Ignatio Sancho-Martinez, Andrew Phimister, H. Martin Seidel, Michael K. Badman, Sean B. Joseph, Bryan Laffitte, Valentina Molteni
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Thomas Knoepfel, Pierre Nimsgern, Sebastien Jacquier, Marjorie Bourrel, Eric Vangrevelinghe, Ralf Glatthar, Dirk Behnke, Phil B. Alper, Pierre-Yves Michellys, Jonathan Deane, Tobias Junt, Geraldine Zipfel, Sarah Limonta, Stuart Hawtin, Cedric Andre, Thomas Boulay, Pius Loetscher, Michael Faller, Jutta Blank, Roland Feifel, Claudia Betschart
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Phil B. Alper, Jonathan Deane, Claudia Betschart, David Buffet, Geraldine Collignon Zipfel, Perry Gordon, Janice Hampton, Stuart Hawtin, Maureen Ibanez, Tao Jiang, Tobias Junt, Thomas Knoepfel, Bo Liu, Jillian Maginnis, Una McKeever, Pierre-Yves Michellys, Daniel Mutnick, Bishnu Nayak, Satoru Niwa, Wendy Richmond, James S. Rush, Peter Syka, Yi Zhang, Xuefeng Zhu
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2020)
Article
Chemistry, Multidisciplinary
Zhipeng Zhang, Maxim Ratnikov, Glen Spraggon, Phil B. Alper
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2018)