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

Minhee Kim, Inseon Hwang, Haushabhau S. Pagire, Suvarna H. Pagire, Wonsuk Choi, Won Gun Choi, Jihyeon Yoon, Won Mi Lee, Jin Sook Song, Eun Kyung Yoo, Seung Mi Lee, Mi Jin Kim, Myung Ae Bae, Dooseop Kim, Heejong Lee, Eun Young Lee, Jae Han Jeon, In Kyu Lee, Hail Kim, Jin Hee Ahn

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10 Scopus citations

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.

Original languageEnglish
Pages (from-to)4171-4182
Number of pages12
JournalJournal of Medicinal Chemistry
Volume63
Issue number8
DOIs
StatePublished - 23 Apr 2020

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