{"title":"基于维生素D的选择性SREBP/SCAP抑制剂KK-052†的结构-活性关系研究","authors":"Fumihiro Kawagoe, Sayuri Mototani, Aileen Mendoza, Yasushi Takemoto, Motonari Uesugi and Atsushi Kittaka","doi":"10.1039/D3MD00352C","DOIUrl":null,"url":null,"abstract":"<p >Vitamin D<small><sub>3</sub></small> metabolites block lipid biosynthesis by promoting degradation of the complex of sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP) independent of their effects on the vitamin D receptor (VDR). We previously reported the development of KK-052, the first vitamin D-based SREBP inhibitor that mitigates hepatic lipid accumulation without VDR-mediated calcemic action in mice. Herein we extend our previous work to synthesize KK-052 analogues. Various substituents were introduced to the phenyl ring of KK-052, and two KK-052 analogues were found to exhibit more potent SREBP/SCAP inhibitory activity than KK-052, whereas they all lack VDR activity. These new KK-052 analogues may be suited for further development as VDR-silent SREBP/SCAP inhibitors.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 10","pages":" 2030-2034"},"PeriodicalIF":3.5970,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Structure–activity relationship studies on vitamin D-based selective SREBP/SCAP inhibitor KK-052†\",\"authors\":\"Fumihiro Kawagoe, Sayuri Mototani, Aileen Mendoza, Yasushi Takemoto, Motonari Uesugi and Atsushi Kittaka\",\"doi\":\"10.1039/D3MD00352C\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Vitamin D<small><sub>3</sub></small> metabolites block lipid biosynthesis by promoting degradation of the complex of sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP) independent of their effects on the vitamin D receptor (VDR). We previously reported the development of KK-052, the first vitamin D-based SREBP inhibitor that mitigates hepatic lipid accumulation without VDR-mediated calcemic action in mice. Herein we extend our previous work to synthesize KK-052 analogues. Various substituents were introduced to the phenyl ring of KK-052, and two KK-052 analogues were found to exhibit more potent SREBP/SCAP inhibitory activity than KK-052, whereas they all lack VDR activity. These new KK-052 analogues may be suited for further development as VDR-silent SREBP/SCAP inhibitors.</p>\",\"PeriodicalId\":88,\"journal\":{\"name\":\"MedChemComm\",\"volume\":\" 10\",\"pages\":\" 2030-2034\"},\"PeriodicalIF\":3.5970,\"publicationDate\":\"2023-08-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"MedChemComm\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2023/md/d3md00352c\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"Pharmacology, Toxicology and Pharmaceutics\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"MedChemComm","FirstCategoryId":"3","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2023/md/d3md00352c","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Pharmacology, Toxicology and Pharmaceutics","Score":null,"Total":0}
Structure–activity relationship studies on vitamin D-based selective SREBP/SCAP inhibitor KK-052†
Vitamin D3 metabolites block lipid biosynthesis by promoting degradation of the complex of sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP) independent of their effects on the vitamin D receptor (VDR). We previously reported the development of KK-052, the first vitamin D-based SREBP inhibitor that mitigates hepatic lipid accumulation without VDR-mediated calcemic action in mice. Herein we extend our previous work to synthesize KK-052 analogues. Various substituents were introduced to the phenyl ring of KK-052, and two KK-052 analogues were found to exhibit more potent SREBP/SCAP inhibitory activity than KK-052, whereas they all lack VDR activity. These new KK-052 analogues may be suited for further development as VDR-silent SREBP/SCAP inhibitors.
期刊介绍：
Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry.
In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.
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