2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of New Peripheral 5HT2A Antagonists for Nonalcoholic Fatty Liver Disease

Design, Synthesis, and Biological Evaluation of New Peripheral 5HT2A Antagonists for Nonalcoholic Fatty Liver Disease

  • J Med Chem. 2020 Apr 23;63(8):4171-4182. doi: 10.1021/acs.jmedchem.0c00002.
Minhee Kim 1,  Inseon Hwang 2,  Haushabhau S Pagire 1,  Suvarna H Pagire 1,  Wonsuk Choi 2,  Won Gun Choi 2,  Jihyeon Yoon 1,  Won Mi Lee 1,  Jin Sook Song 3,  Eun Kyung Yoo 4,  Seung Mi Lee 4,  Mi-Jin Kim 4,  Myung Ae Bae 3,  Dooseop Kim 5,  Heejong Lee 5,  Eun-Young Lee 5,  Jae-Han Jeon 4 6,  In-Kyu Lee 4 6,  Hail Kim 2,  Jin Hee Ahn 1 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
  • 2 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
  • 3 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
  • 4 Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41010, Republic of Korea.
  • 5 R&D center, JD Bioscience, 123 Cheomdan-dwagiro, Buk-gu, Gwangju 61005, Republic of Korea.
  • 6 Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea.
PMID: 32285676 DOI: 10.1021/acs.jmedchem.0c00002
Abstract

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent worldwide, causing serious liver complications, including nonalcoholic steatohepatitis. Recent findings suggest that peripheral serotonin (5-hydroxytryptamine, 5HT) regulates energy homeostasis, including hepatic lipid metabolism. More specifically, liver-specific 5HT2A knockout mice exhibit alleviated hepatic lipid accumulation and hepatic steatosis. Here, structural modifications of pimavanserin (CNS drug), a 5HT2A antagonist approved for Parkinson's disease, led us to synthesize new peripherally acting 5HT2A antagonists. Among the synthesized compounds, compound 14a showed good in vitro activity, good liver microsomal stability, 5HT subtype selectivity, and no significant inhibition of CYP and hERG. The in vitro and in vivo blood-brain barrier permeability study proved that 14a acts peripherally. Compound 14a decreased the liver weight and hepatic lipid accumulation in high-fat-diet-induced obesity mice. Our study suggests new therapeutic possibilities for peripheral 5HT2A antagonists in NAFLD.

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