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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.

Affiliations

Haushabhau S Pagire # 1 2, Suvarna H Pagire # 1 2, Byung-Kwan Jeong # 3, Won-Il Choi # 3, Chang Joo Oh 4, Chae Won Lim 5, Minhee Kim 1, Jihyeon Yoon 1, Seong Soon Kim 6, Myung Ae Bae 6, Jae-Han Jeon 4 7, Sungmin Song 2, Hee Jong Lee 2, Eun Young Lee 2, Peter C Goughnour 2, Dooseop Kim 2, In-Kyu Lee 4 8, Rohit Loomba 9, Hail Kim 10 11, Jin Hee Ahn 12 13
1Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
2JD Bioscience Inc., TJS Knowledge Industrial Center Suite 801, 208 Beon-gil Cheomdangwagi-ro, Buk-gu, Gwangju, 61011, Republic of Korea.
3Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea.
4Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, 41404, Republic of Korea.
5Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, 41404, Republic of Korea.
6Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea.
7Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, 41404, Republic of Korea.
8Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea.
9NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, CA, 92093, USA.
10Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea. hailkim@kaist.edu.
11Biomedical Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea. hailkim@kaist.edu.
12Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea. jhahn@gist.ac.kr.
13JD Bioscience Inc., TJS Knowledge Industrial Center Suite 801, 208 Beon-gil Cheomdangwagi-ro, Buk-gu, Gwangju, 61011, Republic of Korea. jhahn@gist.ac.kr.
#Contributed equally.