Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis
Abstract Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is currently the leading cause of chronic liver disease worldwide. Metabolic Dysfunction-Associated Steatohepatitis (MASH), an advanced form of MASLD, can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Ba...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-44874-3 |
| _version_ | 1827377245750034432 |
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| author | Haushabhau S. Pagire Suvarna H. Pagire Byung-kwan Jeong Won-Il Choi Chang Joo Oh Chae Won Lim Minhee Kim Jihyeon Yoon Seong Soon Kim Myung Ae Bae Jae-Han Jeon Sungmin Song Hee Jong Lee Eun Young Lee Peter C. Goughnour Dooseop Kim In-Kyu Lee Rohit Loomba Hail Kim Jin Hee Ahn |
| author_facet | Haushabhau S. Pagire Suvarna H. Pagire Byung-kwan Jeong Won-Il Choi Chang Joo Oh Chae Won Lim Minhee Kim Jihyeon Yoon Seong Soon Kim Myung Ae Bae Jae-Han Jeon Sungmin Song Hee Jong Lee Eun Young Lee Peter C. Goughnour Dooseop Kim In-Kyu Lee Rohit Loomba Hail Kim Jin Hee Ahn |
| author_sort | Haushabhau S. Pagire |
| collection | DOAJ |
| description | Abstract Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is currently the leading cause of chronic liver disease worldwide. Metabolic Dysfunction-Associated Steatohepatitis (MASH), an advanced form of MASLD, can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Based on recent findings by our team that liver 5HT2A knockout male mice suppressed steatosis and reduced fibrosis-related gene expression, we developed a peripheral 5HT2A antagonist, compound 11c for MASH. It shows good in vitro activity, stability, and in vivo pharmacokinetics (PK) in rats and dogs. Compound 11c also shows good in vivo efficacy in a diet-induced obesity (DIO) male mice model and in a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) male mice model, effectively improving histologic features of MASH and fibrosis. According to the tissue distribution study using [14C]-labeled 11c, the compound was determined to be a peripheral 5HT2A antagonist. Collectively, first-in-class compound 11c shows promise as a therapeutic agent for the treatment of MASLD and MASH. |
| first_indexed | 2024-03-08T12:36:16Z |
| format | Article |
| id | doaj.art-36eae50bb8a2427487532c83a1c7cd4e |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T12:36:16Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-36eae50bb8a2427487532c83a1c7cd4e2024-01-21T12:25:53ZengNature PortfolioNature Communications2041-17232024-01-0115111210.1038/s41467-024-44874-3Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitisHaushabhau S. Pagire0Suvarna H. Pagire1Byung-kwan Jeong2Won-Il Choi3Chang Joo Oh4Chae Won Lim5Minhee Kim6Jihyeon Yoon7Seong Soon Kim8Myung Ae Bae9Jae-Han Jeon10Sungmin Song11Hee Jong Lee12Eun Young Lee13Peter C. Goughnour14Dooseop Kim15In-Kyu Lee16Rohit Loomba17Hail Kim18Jin Hee Ahn19Department of Chemistry, Gwangju Institute of Science and TechnologyDepartment of Chemistry, Gwangju Institute of Science and TechnologyGraduate School of Medical Science and Engineering, Korea Advanced Institute of Science and TechnologyGraduate School of Medical Science and Engineering, Korea Advanced Institute of Science and TechnologyResearch Institute of Aging and Metabolism, Kyungpook National University School of MedicineLeading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University HospitalDepartment of Chemistry, Gwangju Institute of Science and TechnologyDepartment of Chemistry, Gwangju Institute of Science and TechnologyBio & Drug Discovery Division, Korea Research Institute of Chemical TechnologyBio & Drug Discovery Division, Korea Research Institute of Chemical TechnologyResearch Institute of Aging and Metabolism, Kyungpook National University School of MedicineJD Bioscience Inc., TJS Knowledge Industrial Center Suite 801JD Bioscience Inc., TJS Knowledge Industrial Center Suite 801JD Bioscience Inc., TJS Knowledge Industrial Center Suite 801JD Bioscience Inc., TJS Knowledge Industrial Center Suite 801JD Bioscience Inc., TJS Knowledge Industrial Center Suite 801Research Institute of Aging and Metabolism, Kyungpook National University School of MedicineNAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San DiegoGraduate School of Medical Science and Engineering, Korea Advanced Institute of Science and TechnologyDepartment of Chemistry, Gwangju Institute of Science and TechnologyAbstract Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is currently the leading cause of chronic liver disease worldwide. Metabolic Dysfunction-Associated Steatohepatitis (MASH), an advanced form of MASLD, can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Based on recent findings by our team that liver 5HT2A knockout male mice suppressed steatosis and reduced fibrosis-related gene expression, we developed a peripheral 5HT2A antagonist, compound 11c for MASH. It shows good in vitro activity, stability, and in vivo pharmacokinetics (PK) in rats and dogs. Compound 11c also shows good in vivo efficacy in a diet-induced obesity (DIO) male mice model and in a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) male mice model, effectively improving histologic features of MASH and fibrosis. According to the tissue distribution study using [14C]-labeled 11c, the compound was determined to be a peripheral 5HT2A antagonist. Collectively, first-in-class compound 11c shows promise as a therapeutic agent for the treatment of MASLD and MASH.https://doi.org/10.1038/s41467-024-44874-3 |
| spellingShingle | Haushabhau S. Pagire Suvarna H. Pagire Byung-kwan Jeong Won-Il Choi Chang Joo Oh Chae Won Lim Minhee Kim Jihyeon Yoon Seong Soon Kim Myung Ae Bae Jae-Han Jeon Sungmin Song Hee Jong Lee Eun Young Lee Peter C. Goughnour Dooseop Kim In-Kyu Lee Rohit Loomba Hail Kim Jin Hee Ahn Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis Nature Communications |
| title | Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis |
| title_full | Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis |
| title_fullStr | Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis |
| title_full_unstemmed | Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis |
| title_short | Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis |
| title_sort | discovery of a peripheral 5ht2a antagonist as a clinical candidate for metabolic dysfunction associated steatohepatitis |
| url | https://doi.org/10.1038/s41467-024-44874-3 |
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