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

Autor: Won Gun Choi, Jin Sook Song, Hail Kim, Dooseop Kim, Jin Hee Ahn, Myung Ae Bae, Wonsuk Choi, Heejong Lee, Minhee Kim, Jae-Han Jeon, Inkyu Lee, Haushabhau S. Pagire, Inseon Hwang, Eun Kyung Yoo, Jihyeon Yoon, Seung Mi Lee, Won Mi Lee, Eun Young Lee, Mi Jin Kim, Suvarna H. Pagire
Rok vydání: 2020
Předmět:
Zdroj: Journal of Medicinal Chemistry. 63:4171-4182
ISSN: 1520-4804
0022-2623
DOI: 10.1021/acs.jmedchem.0c00002
Popis: 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.
Databáze: OpenAIRE