Synthesis and Biological Activity of New 3-Hydroxy-3-methylglutaryl-CoA Synthase Inhibitors : 2-Oxetanones with a Side Chain Mimicking the Extended Structure of 1233A
Structural analogs of 1233A, a microbial metabolite inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, were designed and synthesized. The 2-oxetanone moiety was left intact. All analogs prepared were tested for inhibition of HMG-CoA synthase activity and sterol synthesis in mouse l...
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| Veröffentlicht in: | Chemical & pharmaceutical bulletin 1994/10/15, Vol.42(10), pp.2097-2107 |
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| container_title | Chemical & pharmaceutical bulletin |
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| creator | HASHIZUME, Hirokazu ITO, Hajime MORIKAWA, Tadanori KANAYA, Naoaki NAGASHIMA, Hajime USUI, Hiroyuki TOMODA, Hiroshi SUNAZUKA, Toshiaki KUMAGAI, Hidetoshi OMURA, Satoshi |
| description | Structural analogs of 1233A, a microbial metabolite inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, were designed and synthesized. The 2-oxetanone moiety was left intact. All analogs prepared were tested for inhibition of HMG-CoA synthase activity and sterol synthesis in mouse liver and for effect on serum triglyceride levels. Of these analogs, trans-4-[2-[3-(7-carboxy-2-naphthyl)phenyl]ethyl]-3-hydroxymethyl-2-oxetanone (4a) showed the highest inhibitory activity in vitro, and also had in vivo inhibitory activity without causing any increase in triglyceride level. |
| doi_str_mv | 10.1248/cpb.42.2097 |
| format | Article |
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The 2-oxetanone moiety was left intact. All analogs prepared were tested for inhibition of HMG-CoA synthase activity and sterol synthesis in mouse liver and for effect on serum triglyceride levels. Of these analogs, trans-4-[2-[3-(7-carboxy-2-naphthyl)phenyl]ethyl]-3-hydroxymethyl-2-oxetanone (4a) showed the highest inhibitory activity in vitro, and also had in vivo inhibitory activity without causing any increase in triglyceride level.</description><identifier>ISSN: 0009-2363</identifier><identifier>EISSN: 1347-5223</identifier><identifier>DOI: 10.1248/cpb.42.2097</identifier><identifier>PMID: 7805135</identifier><identifier>CODEN: CPBTAL</identifier><language>eng</language><publisher>Tokyo: The Pharmaceutical Society of Japan</publisher><subject>1233A analog ; Animals ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; Biological and medical sciences ; cholesterol biosynthesis ; Drug Design ; Fatty Acids, Unsaturated - chemistry ; Fatty Acids, Unsaturated - pharmacology ; General and cellular metabolism. Vitamins ; HMG-CoA synthase ; Hydroxymethylglutaryl-CoA Synthase - antagonists & inhibitors ; In Vitro Techniques ; inhibitor ; Lactones - chemistry ; Lactones - pharmacology ; Liver - drug effects ; Medical sciences ; Mice ; Pharmacology. Drug treatments ; relationship ; Stereoisomerism ; structure-activity ; Structure-Activity Relationship ; triglyceride level ; Triglycerides - blood</subject><ispartof>Chemical and Pharmaceutical Bulletin, 1994/10/15, Vol.42(10), pp.2097-2107</ispartof><rights>The Pharmaceutical Society of Japan</rights><rights>1995 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-957ca83c4e02532bec1a7ef1c7b5110ed028f92ef4d0b48efde019e7ef7446523</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,1884,27929,27930</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3637414$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7805135$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>HASHIZUME, Hirokazu</creatorcontrib><creatorcontrib>ITO, Hajime</creatorcontrib><creatorcontrib>MORIKAWA, Tadanori</creatorcontrib><creatorcontrib>KANAYA, Naoaki</creatorcontrib><creatorcontrib>NAGASHIMA, Hajime</creatorcontrib><creatorcontrib>USUI, Hiroyuki</creatorcontrib><creatorcontrib>TOMODA, Hiroshi</creatorcontrib><creatorcontrib>SUNAZUKA, Toshiaki</creatorcontrib><creatorcontrib>KUMAGAI, Hidetoshi</creatorcontrib><creatorcontrib>OMURA, Satoshi</creatorcontrib><title>Synthesis and Biological Activity of New 3-Hydroxy-3-methylglutaryl-CoA Synthase Inhibitors : 2-Oxetanones with a Side Chain Mimicking the Extended Structure of 1233A</title><title>Chemical & pharmaceutical bulletin</title><addtitle>Chem. Pharm. Bull.</addtitle><description>Structural analogs of 1233A, a microbial metabolite inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, were designed and synthesized. The 2-oxetanone moiety was left intact. All analogs prepared were tested for inhibition of HMG-CoA synthase activity and sterol synthesis in mouse liver and for effect on serum triglyceride levels. Of these analogs, trans-4-[2-[3-(7-carboxy-2-naphthyl)phenyl]ethyl]-3-hydroxymethyl-2-oxetanone (4a) showed the highest inhibitory activity in vitro, and also had in vivo inhibitory activity without causing any increase in triglyceride level.</description><subject>1233A analog</subject><subject>Animals</subject><subject>Anti-Bacterial Agents - chemistry</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>cholesterol biosynthesis</subject><subject>Drug Design</subject><subject>Fatty Acids, Unsaturated - chemistry</subject><subject>Fatty Acids, Unsaturated - pharmacology</subject><subject>General and cellular metabolism. Vitamins</subject><subject>HMG-CoA synthase</subject><subject>Hydroxymethylglutaryl-CoA Synthase - antagonists & inhibitors</subject><subject>In Vitro Techniques</subject><subject>inhibitor</subject><subject>Lactones - chemistry</subject><subject>Lactones - pharmacology</subject><subject>Liver - drug effects</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Pharmacology. Drug treatments</subject><subject>relationship</subject><subject>Stereoisomerism</subject><subject>structure-activity</subject><subject>Structure-Activity Relationship</subject><subject>triglyceride level</subject><subject>Triglycerides - blood</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkc2O0zAUhS0EGsrAijWSF4gNcvFvk7Ar1Qwz0sAsCuvIcW4aD4nTsR2meSGeE4dWZWMvzqdz7r0HobeMLhmX-Sezr5aSLzktsmdowYTMiOJcPEcLSmlBuFiJl-hVCA-UckUzcYEuspwqJtQC_dlOLrYQbMDa1fiLHbphZ43u8NpE-9vGCQ8N_g5PWJCbqfbDYSKC9BDbqdt1Y9R-6shmWON_PjoAvnWtrWwcfMCfMSf3B4jaDQ4CfrKxxRpvbQ1402rr8DfbW_PLuh1OM-CrQwRXQ4230Y8mjh7mbMaFWL9GLxrdBXhz-i_Rz-urH5sbcnf_9XazviNG0TySQmVG58JISJsKXoFhOoOGmaxSjFGoKc-bgkMja1rJHJoaKCsgIZmUK8XFJfpw9N374XGEEMveBgNdpx0MYyizVcGoUEUCPx5B44cQPDTl3ts-XaNktJxbKVMrpeTl3Eqi351sx6qH-syeakj6-5OuQ7p947UzNpyxVGAmmUzY9RF7CFHv4KxrH63pYI5khcrn2DTF8Z3z_wOt9iU48RdzPa5K</recordid><startdate>19941001</startdate><enddate>19941001</enddate><creator>HASHIZUME, Hirokazu</creator><creator>ITO, Hajime</creator><creator>MORIKAWA, Tadanori</creator><creator>KANAYA, Naoaki</creator><creator>NAGASHIMA, Hajime</creator><creator>USUI, Hiroyuki</creator><creator>TOMODA, Hiroshi</creator><creator>SUNAZUKA, Toshiaki</creator><creator>KUMAGAI, Hidetoshi</creator><creator>OMURA, Satoshi</creator><general>The Pharmaceutical Society of Japan</general><general>Maruzen</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>19941001</creationdate><title>Synthesis and Biological Activity of New 3-Hydroxy-3-methylglutaryl-CoA Synthase Inhibitors : 2-Oxetanones with a Side Chain Mimicking the Extended Structure of 1233A</title><author>HASHIZUME, Hirokazu ; ITO, Hajime ; MORIKAWA, Tadanori ; KANAYA, Naoaki ; NAGASHIMA, Hajime ; USUI, Hiroyuki ; TOMODA, Hiroshi ; SUNAZUKA, Toshiaki ; KUMAGAI, Hidetoshi ; OMURA, Satoshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-957ca83c4e02532bec1a7ef1c7b5110ed028f92ef4d0b48efde019e7ef7446523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>1233A analog</topic><topic>Animals</topic><topic>Anti-Bacterial Agents - chemistry</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>cholesterol biosynthesis</topic><topic>Drug Design</topic><topic>Fatty Acids, Unsaturated - chemistry</topic><topic>Fatty Acids, Unsaturated - pharmacology</topic><topic>General and cellular metabolism. Vitamins</topic><topic>HMG-CoA synthase</topic><topic>Hydroxymethylglutaryl-CoA Synthase - antagonists & inhibitors</topic><topic>In Vitro Techniques</topic><topic>inhibitor</topic><topic>Lactones - chemistry</topic><topic>Lactones - pharmacology</topic><topic>Liver - drug effects</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Pharmacology. 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Pharm. Bull.</addtitle><date>1994-10-01</date><risdate>1994</risdate><volume>42</volume><issue>10</issue><spage>2097</spage><epage>2107</epage><pages>2097-2107</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><coden>CPBTAL</coden><abstract>Structural analogs of 1233A, a microbial metabolite inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, were designed and synthesized. The 2-oxetanone moiety was left intact. All analogs prepared were tested for inhibition of HMG-CoA synthase activity and sterol synthesis in mouse liver and for effect on serum triglyceride levels. Of these analogs, trans-4-[2-[3-(7-carboxy-2-naphthyl)phenyl]ethyl]-3-hydroxymethyl-2-oxetanone (4a) showed the highest inhibitory activity in vitro, and also had in vivo inhibitory activity without causing any increase in triglyceride level.</abstract><cop>Tokyo</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>7805135</pmid><doi>10.1248/cpb.42.2097</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; J-STAGE (Japan Science & Technology Information Aggregator, Electronic) Freely Available Titles - Japanese; Free Full-Text Journals in Chemistry |
| subjects | 1233A analog Animals Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Biological and medical sciences cholesterol biosynthesis Drug Design Fatty Acids, Unsaturated - chemistry Fatty Acids, Unsaturated - pharmacology General and cellular metabolism. Vitamins HMG-CoA synthase Hydroxymethylglutaryl-CoA Synthase - antagonists & inhibitors In Vitro Techniques inhibitor Lactones - chemistry Lactones - pharmacology Liver - drug effects Medical sciences Mice Pharmacology. Drug treatments relationship Stereoisomerism structure-activity Structure-Activity Relationship triglyceride level Triglycerides - blood |
| title | Synthesis and Biological Activity of New 3-Hydroxy-3-methylglutaryl-CoA Synthase Inhibitors : 2-Oxetanones with a Side Chain Mimicking the Extended Structure of 1233A |
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