Synthesis and biological evaluation of tyrosine derivatives as peripheral 5HT2A receptor antagonists for nonalcoholic fatty liver disease

Minhee Kim; Wonil Choi; Jihyeon Yoon; Byung-Kwan Jeong; Suvarna H Pagire; Haushabhau S Pagire; Jungsun Park; Jung Eun Nam; Chang Joo Oh; Jae-Han Jeon; Seong Soon Kim; Byung Hoi Lee; Jin Sook Song; Myung Ae Bae; In-Kyu Lee; Hail Kim; Jin Hee Ahn

doi:10.1016/j.ejmech.2022.114517

Synthesis and biological evaluation of tyrosine derivatives as peripheral 5HT_2A receptor antagonists for nonalcoholic fatty liver disease

Eur J Med Chem. 2022 Sep 5:239:114517. doi: 10.1016/j.ejmech.2022.114517. Epub 2022 Jun 15.

Authors

Minhee Kim¹, Wonil Choi², Jihyeon Yoon¹, Byung-Kwan Jeong², Suvarna H Pagire¹, Haushabhau S Pagire¹, Jungsun Park², Jung Eun Nam², Chang Joo Oh³, Jae-Han Jeon⁴, Seong Soon Kim⁵, Byung Hoi Lee⁵, Jin Sook Song⁵, Myung Ae Bae⁵, In-Kyu Lee⁶, Hail Kim⁷, Jin Hee Ahn⁸

Affiliations

¹ Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea.
² Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, South Korea; Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, 34141, South Korea.
³ Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, South Korea.
⁴ Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, South Korea; Department of Internal Medicine, Kyungpook National University Hospital and School of Medicine, Kyungpook National University, Daegu, 700-721, South Korea.
⁵ Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
⁶ Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, South Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea.
⁷ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, South Korea; Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, 34141, South Korea. Electronic address: hailkim@kaist.ac.kr.
⁸ Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea; JD Bioscience, 208 Cheomdan-dwagiro, Buk-gu, Gwangju, 61005, South Korea. Electronic address: jhahn@gist.ac.kr.

PMID: 35732081
DOI: 10.1016/j.ejmech.2022.114517

Abstract

Non-alcoholic fatty liver disease (NAFLD), attributed to excessive fat accumulation in the liver, is reportedly prevalent worldwide. NAFLD is one of the leading causes of chronic liver disease, including non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatic cellular carcinoma (HCC). The peripheral roles of serotonin (5-hydroxytryptamine, 5HT) were found to regulate hepatic lipid metabolism. Among serotonin receptor subtypes, 5HT_2A receptor is known to regulate hepatic lipid metabolism. Hepatic lipid accumulation and hepatic triglyceride (TG) were reduced in liver-specific 5HT_2A receptor knockout (5HT_2A receptor LKO) mice upon high-fat diet (HFD) feeding. In the present study, we explored a series of new peripherally acting 5HT_2A receptor antagonists. Compound 14a displayed good in vitro activity, with an IC₅₀ value of 0.17 nM. Compound 14a exhibited good microsomal stability, no significant CYP and hERG inhibition, and 5HT receptor subtype selectivity. The brain-to-plasma ratio of 14a was below the lower limit of quantification, indicating limited blood-brain barrier (BBB) penetration. HFD-fed 14a treated mice showed decreased liver steatosis and lobular inflammation. These results demonstrate the potential of newly synthesized peripheral 5HT_2A receptor antagonists for treating NAFLD.

Keywords: Antagonist; Blood-brain barrier (BBB); Non-alcoholic fatty liver disease (NAFLD); Serotonin receptor 2A (5HT2A receptor); Treatment.

MeSH terms

Animals
Carcinoma, Hepatocellular* / pathology
Diet, High-Fat / adverse effects
Liver / metabolism
Liver Neoplasms* / pathology
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease* / drug therapy
Non-alcoholic Fatty Liver Disease* / etiology
Serotonin / metabolism
Tyrosine / metabolism

Substances

Serotonin
Tyrosine