Design, Synthesis, and Biological Evaluation of New Peripheral 5HT 2A Antagonists for Nonalcoholic Fatty Liver Disease
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. Mo...
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| Veröffentlicht in: | Journal of medicinal chemistry 2020-04, Vol.63 (8), p.4171-4182 |
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| creator | Kim, Minhee Hwang, Inseon Pagire, Haushabhau S Pagire, Suvarna H Choi, Wonsuk Choi, Won Gun Yoon, Jihyeon Lee, Won Mi Song, Jin Sook Yoo, Eun Kyung Lee, Seung Mi Kim, Mi-Jin Bae, Myung Ae Kim, Dooseop Lee, Heejong Lee, Eun-Young Jeon, Jae-Han Lee, In-Kyu Kim, Hail Ahn, Jin Hee |
| description | 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 5HT
knockout mice exhibit alleviated hepatic lipid accumulation and hepatic steatosis. Here, structural modifications of pimavanserin (CNS drug), a 5HT
antagonist approved for Parkinson's disease, led us to synthesize new peripherally acting 5HT
antagonists. Among the synthesized compounds, compound
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
acts peripherally. Compound
decreased the liver weight and hepatic lipid accumulation in high-fat-diet-induced obesity mice. Our study suggests new therapeutic possibilities for peripheral 5HT
antagonists in NAFLD. |
| doi_str_mv | 10.1021/acs.jmedchem.0c00002 |
| format | Article |
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knockout mice exhibit alleviated hepatic lipid accumulation and hepatic steatosis. Here, structural modifications of pimavanserin (CNS drug), a 5HT
antagonist approved for Parkinson's disease, led us to synthesize new peripherally acting 5HT
antagonists. Among the synthesized compounds, compound
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
acts peripherally. Compound
decreased the liver weight and hepatic lipid accumulation in high-fat-diet-induced obesity mice. Our study suggests new therapeutic possibilities for peripheral 5HT
antagonists in NAFLD.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.0c00002</identifier><identifier>PMID: 32285676</identifier><language>eng</language><publisher>United States</publisher><ispartof>Journal of medicinal chemistry, 2020-04, Vol.63 (8), p.4171-4182</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1196-7131ccb0f8b754bb36b6b87ace2850660f30c18bf65a98297437cdcc5a21a8fb3</citedby><cites>FETCH-LOGICAL-c1196-7131ccb0f8b754bb36b6b87ace2850660f30c18bf65a98297437cdcc5a21a8fb3</cites><orcidid>0000-0001-5384-7342 ; 0000-0002-6957-6062</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,2752,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32285676$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Minhee</creatorcontrib><creatorcontrib>Hwang, Inseon</creatorcontrib><creatorcontrib>Pagire, Haushabhau S</creatorcontrib><creatorcontrib>Pagire, Suvarna H</creatorcontrib><creatorcontrib>Choi, Wonsuk</creatorcontrib><creatorcontrib>Choi, Won Gun</creatorcontrib><creatorcontrib>Yoon, Jihyeon</creatorcontrib><creatorcontrib>Lee, Won Mi</creatorcontrib><creatorcontrib>Song, Jin Sook</creatorcontrib><creatorcontrib>Yoo, Eun Kyung</creatorcontrib><creatorcontrib>Lee, Seung Mi</creatorcontrib><creatorcontrib>Kim, Mi-Jin</creatorcontrib><creatorcontrib>Bae, Myung Ae</creatorcontrib><creatorcontrib>Kim, Dooseop</creatorcontrib><creatorcontrib>Lee, Heejong</creatorcontrib><creatorcontrib>Lee, Eun-Young</creatorcontrib><creatorcontrib>Jeon, Jae-Han</creatorcontrib><creatorcontrib>Lee, In-Kyu</creatorcontrib><creatorcontrib>Kim, Hail</creatorcontrib><creatorcontrib>Ahn, Jin Hee</creatorcontrib><title>Design, Synthesis, and Biological Evaluation of New Peripheral 5HT 2A Antagonists for Nonalcoholic Fatty Liver Disease</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>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 5HT
knockout mice exhibit alleviated hepatic lipid accumulation and hepatic steatosis. Here, structural modifications of pimavanserin (CNS drug), a 5HT
antagonist approved for Parkinson's disease, led us to synthesize new peripherally acting 5HT
antagonists. Among the synthesized compounds, compound
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
acts peripherally. Compound
decreased the liver weight and hepatic lipid accumulation in high-fat-diet-induced obesity mice. Our study suggests new therapeutic possibilities for peripheral 5HT
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knockout mice exhibit alleviated hepatic lipid accumulation and hepatic steatosis. Here, structural modifications of pimavanserin (CNS drug), a 5HT
antagonist approved for Parkinson's disease, led us to synthesize new peripherally acting 5HT
antagonists. Among the synthesized compounds, compound
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
acts peripherally. Compound
decreased the liver weight and hepatic lipid accumulation in high-fat-diet-induced obesity mice. Our study suggests new therapeutic possibilities for peripheral 5HT
antagonists in NAFLD.</abstract><cop>United States</cop><pmid>32285676</pmid><doi>10.1021/acs.jmedchem.0c00002</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-5384-7342</orcidid><orcidid>https://orcid.org/0000-0002-6957-6062</orcidid></addata></record> |
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| title | Design, Synthesis, and Biological Evaluation of New Peripheral 5HT 2A Antagonists for Nonalcoholic Fatty Liver Disease |
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