Synthesis and Biological Evaluation of Quinuclidine Derivatives Incorporating Phenothiazine Moieties as Squalene Synthase Inhibitors
Squalene synthase inhibitors have the potential to be superior hypocholesterolemic agents. A series of quinuclidine derivatives incorporating phenothiazine systems was synthesized in order to investigate the effects of their structure on the inhibition of hamster liver microsomal enzyme. (±)-3-(10-M...
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| Veröffentlicht in: | Chemical & Pharmaceutical Bulletin 2004, Vol.52(10), pp.1204-1209 |
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| container_title | Chemical & Pharmaceutical Bulletin |
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| creator | Ishihara, Tsukasa Kakuta, Hirotoshi Moritani, Hiroshi Ugawa, Tohru Yanagisawa, Isao |
| description | Squalene synthase inhibitors have the potential to be superior hypocholesterolemic agents. A series of quinuclidine derivatives incorporating phenothiazine systems was synthesized in order to investigate the effects of their structure on the inhibition of hamster liver microsomal enzyme. (±)-3-(10-Methyl-10H-phenothiazin-3-ylmethoxy)quinuclidine hydrochloride (19) was the most potent inhibitor in this series with an IC50 value of 0.12 μM. Oral dosing of compound 19 to hamsters demonstrated effective reduction of both plasma total cholesterol levels and plasma triglyceride levels. Compound 19 showed a reduced tendency to elevate plasma transaminase levels, an indicator of hepatotoxicity. Enantiomerically pure (−)-19, YM-53546, was found to be more potent than the corresponding (+)-enantiomer. |
| doi_str_mv | 10.1248/cpb.52.1204 |
| format | Article |
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A series of quinuclidine derivatives incorporating phenothiazine systems was synthesized in order to investigate the effects of their structure on the inhibition of hamster liver microsomal enzyme. (±)-3-(10-Methyl-10H-phenothiazin-3-ylmethoxy)quinuclidine hydrochloride (19) was the most potent inhibitor in this series with an IC50 value of 0.12 μM. Oral dosing of compound 19 to hamsters demonstrated effective reduction of both plasma total cholesterol levels and plasma triglyceride levels. Compound 19 showed a reduced tendency to elevate plasma transaminase levels, an indicator of hepatotoxicity. Enantiomerically pure (−)-19, YM-53546, was found to be more potent than the corresponding (+)-enantiomer.</description><identifier>ISSN: 0009-2363</identifier><identifier>EISSN: 1347-5223</identifier><identifier>DOI: 10.1248/cpb.52.1204</identifier><identifier>PMID: 15467236</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>Animals ; Anticholesteremic Agents - chemical synthesis ; Anticholesteremic Agents - chemistry ; Anticholesteremic Agents - pharmacology ; Cell Line, Tumor ; Cricetinae ; Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors ; hepatotoxicity ; Humans ; hypocholesterolemic agent ; In Vitro Techniques ; Lipids - blood ; Male ; Mesocricetus ; Microsomes, Liver - drug effects ; Microsomes, Liver - enzymology ; Phenothiazines - chemical synthesis ; Phenothiazines - chemistry ; Phenothiazines - pharmacology ; quinuclidine ; Quinuclidines - chemical synthesis ; Quinuclidines - chemistry ; Quinuclidines - pharmacology ; Rats ; Rats, Inbred F344 ; squalene synthase ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Chemical and Pharmaceutical Bulletin, 2004, Vol.52(10), pp.1204-1209</ispartof><rights>2004 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c667t-f2562ab07e9bd5255b6cb130f04eb069a9da618d7018b7681f3c7664a2d28d23</citedby><cites>FETCH-LOGICAL-c667t-f2562ab07e9bd5255b6cb130f04eb069a9da618d7018b7681f3c7664a2d28d23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,1877,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15467236$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ishihara, Tsukasa</creatorcontrib><creatorcontrib>Kakuta, Hirotoshi</creatorcontrib><creatorcontrib>Moritani, Hiroshi</creatorcontrib><creatorcontrib>Ugawa, Tohru</creatorcontrib><creatorcontrib>Yanagisawa, Isao</creatorcontrib><creatorcontrib>Yamanouchi Pharmaceutical co.Ltd</creatorcontrib><creatorcontrib>Institute for Drug Discovery Research</creatorcontrib><title>Synthesis and Biological Evaluation of Quinuclidine Derivatives Incorporating Phenothiazine Moieties as Squalene Synthase Inhibitors</title><title>Chemical & Pharmaceutical Bulletin</title><addtitle>Chem. Pharm. Bull.</addtitle><description>Squalene synthase inhibitors have the potential to be superior hypocholesterolemic agents. A series of quinuclidine derivatives incorporating phenothiazine systems was synthesized in order to investigate the effects of their structure on the inhibition of hamster liver microsomal enzyme. (±)-3-(10-Methyl-10H-phenothiazin-3-ylmethoxy)quinuclidine hydrochloride (19) was the most potent inhibitor in this series with an IC50 value of 0.12 μM. Oral dosing of compound 19 to hamsters demonstrated effective reduction of both plasma total cholesterol levels and plasma triglyceride levels. Compound 19 showed a reduced tendency to elevate plasma transaminase levels, an indicator of hepatotoxicity. Enantiomerically pure (−)-19, YM-53546, was found to be more potent than the corresponding (+)-enantiomer.</description><subject>Animals</subject><subject>Anticholesteremic Agents - chemical synthesis</subject><subject>Anticholesteremic Agents - chemistry</subject><subject>Anticholesteremic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cricetinae</subject><subject>Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors</subject><subject>hepatotoxicity</subject><subject>Humans</subject><subject>hypocholesterolemic agent</subject><subject>In Vitro Techniques</subject><subject>Lipids - blood</subject><subject>Male</subject><subject>Mesocricetus</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - enzymology</subject><subject>Phenothiazines - chemical synthesis</subject><subject>Phenothiazines - chemistry</subject><subject>Phenothiazines - pharmacology</subject><subject>quinuclidine</subject><subject>Quinuclidines - chemical synthesis</subject><subject>Quinuclidines - chemistry</subject><subject>Quinuclidines - pharmacology</subject><subject>Rats</subject><subject>Rats, Inbred F344</subject><subject>squalene synthase</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUtv1DAUhS0EokNhxR5FQuoGpVy_kyUtpVQqAtTuLcdxJh5l7KmdjFTW_HCcZjSV2Fw_zudzr3wQeo_hHBNWfTa75pyTvAf2Aq0wZbLkhNCXaAUAdUmooCfoTUobAMJB0tfoBHMmZBZW6O_dox97m1wqtG-LCxeGsHZGD8XVXg-THl3wReiK35Pzkxlc67wtvtro9lna21TceBPiLsR89OviV299GHun_8zcj-Ds6DKkU3H3MOnB5sunhjrZ_LJ3jRtDTG_Rq04Pyb47rKfo_tvV_eX38vbn9c3ll9vSCCHHsiNcEN2AtHXTcsJ5I0yDKXTAbAOi1nWrBa5aCbhqpKhwR40UgmnSkqol9BSdLba7GB4mm0a1dcnYYdDehikpIWoqCGUZ_PgfuAlT9Hk0hZkAymrJZ7tPC2ViSCnaTu2i2-r4qDCoORmVk1GcqDmZTH84eE7N1rbP7CGKDFwvQFbnAIIf8h8-dzZJmt5unSIATAFwktsAXuznUmOQWLB5sIvFaZNGvbbHVjqOzgz2OBYc6pPBUex1VNbTf4JjuQc</recordid><startdate>20041001</startdate><enddate>20041001</enddate><creator>Ishihara, Tsukasa</creator><creator>Kakuta, Hirotoshi</creator><creator>Moritani, Hiroshi</creator><creator>Ugawa, Tohru</creator><creator>Yanagisawa, Isao</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</general><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>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20041001</creationdate><title>Synthesis and Biological Evaluation of Quinuclidine Derivatives Incorporating Phenothiazine Moieties as Squalene Synthase Inhibitors</title><author>Ishihara, Tsukasa ; Kakuta, Hirotoshi ; Moritani, Hiroshi ; Ugawa, Tohru ; Yanagisawa, Isao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c667t-f2562ab07e9bd5255b6cb130f04eb069a9da618d7018b7681f3c7664a2d28d23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Anticholesteremic Agents - chemical synthesis</topic><topic>Anticholesteremic Agents - chemistry</topic><topic>Anticholesteremic Agents - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cricetinae</topic><topic>Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors</topic><topic>hepatotoxicity</topic><topic>Humans</topic><topic>hypocholesterolemic agent</topic><topic>In Vitro Techniques</topic><topic>Lipids - blood</topic><topic>Male</topic><topic>Mesocricetus</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - enzymology</topic><topic>Phenothiazines - chemical synthesis</topic><topic>Phenothiazines - chemistry</topic><topic>Phenothiazines - pharmacology</topic><topic>quinuclidine</topic><topic>Quinuclidines - chemical synthesis</topic><topic>Quinuclidines - chemistry</topic><topic>Quinuclidines - pharmacology</topic><topic>Rats</topic><topic>Rats, Inbred F344</topic><topic>squalene synthase</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ishihara, Tsukasa</creatorcontrib><creatorcontrib>Kakuta, Hirotoshi</creatorcontrib><creatorcontrib>Moritani, Hiroshi</creatorcontrib><creatorcontrib>Ugawa, Tohru</creatorcontrib><creatorcontrib>Yanagisawa, Isao</creatorcontrib><creatorcontrib>Yamanouchi Pharmaceutical co.Ltd</creatorcontrib><creatorcontrib>Institute for Drug Discovery Research</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical & Pharmaceutical Bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ishihara, Tsukasa</au><au>Kakuta, Hirotoshi</au><au>Moritani, Hiroshi</au><au>Ugawa, Tohru</au><au>Yanagisawa, Isao</au><aucorp>Yamanouchi Pharmaceutical co.Ltd</aucorp><aucorp>Institute for Drug Discovery Research</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Biological Evaluation of Quinuclidine Derivatives Incorporating Phenothiazine Moieties as Squalene Synthase Inhibitors</atitle><jtitle>Chemical & Pharmaceutical Bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>2004-10-01</date><risdate>2004</risdate><volume>52</volume><issue>10</issue><spage>1204</spage><epage>1209</epage><pages>1204-1209</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><abstract>Squalene synthase inhibitors have the potential to be superior hypocholesterolemic agents. A series of quinuclidine derivatives incorporating phenothiazine systems was synthesized in order to investigate the effects of their structure on the inhibition of hamster liver microsomal enzyme. (±)-3-(10-Methyl-10H-phenothiazin-3-ylmethoxy)quinuclidine hydrochloride (19) was the most potent inhibitor in this series with an IC50 value of 0.12 μM. Oral dosing of compound 19 to hamsters demonstrated effective reduction of both plasma total cholesterol levels and plasma triglyceride levels. Compound 19 showed a reduced tendency to elevate plasma transaminase levels, an indicator of hepatotoxicity. 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| subjects | Animals Anticholesteremic Agents - chemical synthesis Anticholesteremic Agents - chemistry Anticholesteremic Agents - pharmacology Cell Line, Tumor Cricetinae Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors hepatotoxicity Humans hypocholesterolemic agent In Vitro Techniques Lipids - blood Male Mesocricetus Microsomes, Liver - drug effects Microsomes, Liver - enzymology Phenothiazines - chemical synthesis Phenothiazines - chemistry Phenothiazines - pharmacology quinuclidine Quinuclidines - chemical synthesis Quinuclidines - chemistry Quinuclidines - pharmacology Rats Rats, Inbred F344 squalene synthase Stereoisomerism Structure-Activity Relationship |
| title | Synthesis and Biological Evaluation of Quinuclidine Derivatives Incorporating Phenothiazine Moieties as Squalene Synthase Inhibitors |
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