Yu, Donna D. and Van Citters, Gregg and Li, Hongzhi and Stoltz, Brian M. and Forman, Barry M. (2021) Discovery of novel modulators for the PPARα (peroxisome proliferator activated receptor α): Potential therapies for nonalcoholic fatty liver disease. Bioorganic and Medicinal Chemistry, 41 . Art. No. 116193. ISSN 0968-0896. doi:10.1016/j.bmc.2021.116193. https://resolver.caltech.edu/CaltechAUTHORS:20210507-140316316
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a severe liver disease causing serious liver complications, including nonalcoholic steatohepatitis (NASH). Nuclear receptor PPARα (peroxisome proliferator-activated receptor α) has drawn special attention recently as a potential developmental drug target to treat type-2 diabetes and related diseases due to its unique functions in regulating lipid metabolism, promoting triglyceride oxidation, and suppressing hepatic inflammation, raising interest in PPARα agonists as potential therapies for NAFLD. However, how PPARα coordinates potential treatment of NAFLD and NASH between various metabolic pathways is still obscure. Here, we show that the DY series of novel selective PPARα modulators activate PPARα by up-regulating PPARα target genes directly involved in NAFLD and NASH. The design, synthesis, docking studies, and in vitro and in vivo evaluation of the novel DY series of PPARα agonists are described.
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| Additional Information: | © 2021 Elsevier Ltd. Received 9 March 2021, Revised 23 April 2021, Accepted 26 April 2021, Available online 1 May 2021. We gratefully thank Drs. Nancy Chen, James L. Figarola, and Scott C. Virgil for technical assistance. We thank Drs. Daniell Mattern, Kyle Sousa, and Nilay Patel for their encouragement. We thank Benjamin Thoma (SURF Student at California Institute of Technology) for helpful discuss. We also thank City of Hope’s Ruth B. and Robert K. Lanman Chair Endowment and Dr. Arthur Riggs for their support of this work. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | ||||||
| Subject Keywords: | PPARα; NASH; NAFLD; Selective PPARα agonists; Hepatic steatohepatitis | ||||||
| DOI: | 10.1016/j.bmc.2021.116193 | ||||||
| Record Number: | CaltechAUTHORS:20210507-140316316 | ||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20210507-140316316 | ||||||
| Official Citation: | Donna D. Yu, Gregg Van Citters, Hongzhi Li, Brian M. Stoltz, Barry M. Forman, Discovery of novel modulators for the PPARα (peroxisome proliferator activated receptor α): Potential therapies for nonalcoholic fatty liver disease, Bioorganic & Medicinal Chemistry, Volume 41, 2021, 116193, ISSN 0968-0896, https://doi.org/10.1016/j.bmc.2021.116193. (https://www.sciencedirect.com/science/article/pii/S0968089621002017) | ||||||
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||
| ID Code: | 109013 | ||||||
| Collection: | CaltechAUTHORS | ||||||
| Deposited By: | Tony Diaz | ||||||
| Deposited On: | 07 May 2021 21:36 | ||||||
| Last Modified: | 26 May 2021 16:43 |
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