[Title]
Discovery of a peripheral 5HT_2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis

[Author]

SHaushabhau S. Pagire1,2,11, Suvarna H. Pagire1,2,11, Byung-kwan Jeong3,11, Won-Il Choi 3,11, Chang Joo Oh4 , Chae Won Lim5 , Minhee Kim1 , Jihyeon Yoon 1 , Seong Soon Kim 6 , Myung Ae Bae6 , Jae-Han Jeon4,7, Sungmin Song2 , Hee Jong Lee2 , Eun Young Lee2 , Peter C. Goughnour2 , Dooseop Kim2 , In-Kyu Lee 4,8, Rohit Loomba9 , Hail Kim 3,10 & Jin Hee Ahn 1,2

1 Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
2 JD Bioscience Inc., TJS Knowledge Industrial Center Suite 801, 208 Beon-gil Cheomdangwagi-ro, Buk-gu, Gwangju 61011, Republic of Korea.
3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
4 Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu 41404, Republic of Korea.
5 Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Republic of Korea.
6 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea.
7 Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, Republic of Korea.
8 Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea.
9 NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
10Biomedical Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
11These authors contributed equally: Haushabhau S. Pagire, Suvarna H. Pagire, Byung-kwan Jeong, Won-Il Choi. e-mail: hailkim@kaist.edu; jhahn@gist.ac.k

[Journal] 

Nature Communications volume 15, Article number: 645 (2024) 


[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 5HT_2A knockout male mice suppressed steatosis and reduced fibrosis-related gene expression, we developed a peripheral 5HT_2A 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 5HT_2A antagonist. Collectively, first-in-class compound 11c shows promise as a therapeutic agent for the treatment of MASLD and MASH.