1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: A new class of potent and selective aldosterone synthase inhibitors
1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols and related compounds were synthesized and evaluated for inhibition of aldosterone synthase (CYP11B2), a potential target for cardiovascular diseases associated with elevated plasma aldosterone levels like congestive heart failure and myocardial fibr...
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| Veröffentlicht in: | European journal of medicinal chemistry 2015-01, Vol.89, p.597-605 |
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| container_title | European journal of medicinal chemistry |
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| creator | Grombein, Cornelia M. Hu, Qingzhong Heim, Ralf Rau, Sabrina Zimmer, Christina Hartmann, Rolf W. |
| description | 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols and related compounds were synthesized and evaluated for inhibition of aldosterone synthase (CYP11B2), a potential target for cardiovascular diseases associated with elevated plasma aldosterone levels like congestive heart failure and myocardial fibrosis. Introduction of substituents at the phenylsulfinyl moiety and changes of the substitution pattern at the naphthalene core were examined. Potent compounds were further examined for selectivity versus other important steroidogenic CYP enzymes, i.e. the highly homologous 11β-hydroxylase (CYP11B1), CYP17 and CYP19. The most potent compound (IC50 = 14 nM) discovered was the meta-trifluoromethoxy derivative 11, which also exhibited excellent selectivity toward CYP11B1 (SF = 415), and showed no inhibition of CYP17 and CYP19.
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•Inhibition of aldosterone synthase is a superior treatment of cardiovascular diseases.•1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols were synthesized and evaluated.•These compounds are potent aldosterone synthase inhibitors (IC50 |
| doi_str_mv | 10.1016/j.ejmech.2014.10.027 |
| format | Article |
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[Display omitted]
•Inhibition of aldosterone synthase is a superior treatment of cardiovascular diseases.•1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols were synthesized and evaluated.•These compounds are potent aldosterone synthase inhibitors (IC50 < 65 nM).•High selectivity over CYP11B1, CYP17 and CYP19 were achieved.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2014.10.027</identifier><identifier>PMID: 25462268</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols ; 11β-hydroxylase ; Aldosterone ; Aldosterone synthase ; Animals ; Cytochrome P-450 CYP11B2 - antagonists & inhibitors ; Cytochrome P-450 CYP11B2 - metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - classification ; Enzyme Inhibitors - pharmacology ; Humans ; Male ; Models, Molecular ; Naphthols - chemical synthesis ; Naphthols - chemistry ; Naphthols - pharmacology ; Rats ; Rats, Wistar ; Selectivity ; Structure-Activity Relationship ; Sulfoxides - chemical synthesis ; Sulfoxides - chemistry ; Sulfoxides - pharmacology</subject><ispartof>European journal of medicinal chemistry, 2015-01, Vol.89, p.597-605</ispartof><rights>2014 Elsevier Masson SAS</rights><rights>Copyright © 2014 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-7de8f8243bb2b6c0754b273ea9a735afaff7642c4c15752b1a2bd081d1c9d12b3</citedby><cites>FETCH-LOGICAL-c408t-7de8f8243bb2b6c0754b273ea9a735afaff7642c4c15752b1a2bd081d1c9d12b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2014.10.027$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25462268$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Grombein, Cornelia M.</creatorcontrib><creatorcontrib>Hu, Qingzhong</creatorcontrib><creatorcontrib>Heim, Ralf</creatorcontrib><creatorcontrib>Rau, Sabrina</creatorcontrib><creatorcontrib>Zimmer, Christina</creatorcontrib><creatorcontrib>Hartmann, Rolf W.</creatorcontrib><title>1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: A new class of potent and selective aldosterone synthase inhibitors</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols and related compounds were synthesized and evaluated for inhibition of aldosterone synthase (CYP11B2), a potential target for cardiovascular diseases associated with elevated plasma aldosterone levels like congestive heart failure and myocardial fibrosis. Introduction of substituents at the phenylsulfinyl moiety and changes of the substitution pattern at the naphthalene core were examined. Potent compounds were further examined for selectivity versus other important steroidogenic CYP enzymes, i.e. the highly homologous 11β-hydroxylase (CYP11B1), CYP17 and CYP19. The most potent compound (IC50 = 14 nM) discovered was the meta-trifluoromethoxy derivative 11, which also exhibited excellent selectivity toward CYP11B1 (SF = 415), and showed no inhibition of CYP17 and CYP19.
[Display omitted]
•Inhibition of aldosterone synthase is a superior treatment of cardiovascular diseases.•1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols were synthesized and evaluated.•These compounds are potent aldosterone synthase inhibitors (IC50 < 65 nM).•High selectivity over CYP11B1, CYP17 and CYP19 were achieved.</description><subject>1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols</subject><subject>11β-hydroxylase</subject><subject>Aldosterone</subject><subject>Aldosterone synthase</subject><subject>Animals</subject><subject>Cytochrome P-450 CYP11B2 - antagonists & inhibitors</subject><subject>Cytochrome P-450 CYP11B2 - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - classification</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Male</subject><subject>Models, Molecular</subject><subject>Naphthols - chemical synthesis</subject><subject>Naphthols - chemistry</subject><subject>Naphthols - pharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Selectivity</subject><subject>Structure-Activity Relationship</subject><subject>Sulfoxides - chemical synthesis</subject><subject>Sulfoxides - chemistry</subject><subject>Sulfoxides - pharmacology</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtuFDEQRS1ERIbAHyDkZbLwxHa77Q4LpCgKDykSLGBt-VGt9shjN3bPoP57PJrAklWVqu69pToIvWN0yyiTt7st7Pbgpi2nTLTRlnL1Am2YkgPpeC9eog3lvCM978Qlel3rjlLaS0pfocu2lpzLYYOOjHyfIK2xHuIYWiUduZ7XEnxIrV3jTTLztEwmQiKc5Fg_4Huc4Dd20dSK84jnvEBasEkeV4jglnAEbKLPdYGSE-C6phZQAYc0BRuWXOobdDGaWOHtc71CPz89_nj4Qp6-ff76cP9EnKDDQpSHYRy46KzlVjqqemG56sDcGdX1ZjTjqKTgTjjWq55bZrj1dGCeuTvPuO2u0PU5dy751wHqovehOojRJMiHqpnshOJSCdGk4ix1JddaYNRzCXtTVs2oPhHXO30mrk_ET9NGvNneP1842D34f6a_iJvg41kA7c9jgKKrC5Ac-FAaLO1z-P-FP4P_lLs</recordid><startdate>20150107</startdate><enddate>20150107</enddate><creator>Grombein, Cornelia M.</creator><creator>Hu, Qingzhong</creator><creator>Heim, Ralf</creator><creator>Rau, Sabrina</creator><creator>Zimmer, Christina</creator><creator>Hartmann, Rolf W.</creator><general>Elsevier Masson SAS</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>7X8</scope></search><sort><creationdate>20150107</creationdate><title>1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: A new class of potent and selective aldosterone synthase inhibitors</title><author>Grombein, Cornelia M. ; Hu, Qingzhong ; Heim, Ralf ; Rau, Sabrina ; Zimmer, Christina ; Hartmann, Rolf W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-7de8f8243bb2b6c0754b273ea9a735afaff7642c4c15752b1a2bd081d1c9d12b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols</topic><topic>11β-hydroxylase</topic><topic>Aldosterone</topic><topic>Aldosterone synthase</topic><topic>Animals</topic><topic>Cytochrome P-450 CYP11B2 - antagonists & inhibitors</topic><topic>Cytochrome P-450 CYP11B2 - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - classification</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Male</topic><topic>Models, Molecular</topic><topic>Naphthols - chemical synthesis</topic><topic>Naphthols - chemistry</topic><topic>Naphthols - pharmacology</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Selectivity</topic><topic>Structure-Activity Relationship</topic><topic>Sulfoxides - chemical synthesis</topic><topic>Sulfoxides - chemistry</topic><topic>Sulfoxides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grombein, Cornelia M.</creatorcontrib><creatorcontrib>Hu, Qingzhong</creatorcontrib><creatorcontrib>Heim, Ralf</creatorcontrib><creatorcontrib>Rau, Sabrina</creatorcontrib><creatorcontrib>Zimmer, Christina</creatorcontrib><creatorcontrib>Hartmann, Rolf W.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grombein, Cornelia M.</au><au>Hu, Qingzhong</au><au>Heim, Ralf</au><au>Rau, Sabrina</au><au>Zimmer, Christina</au><au>Hartmann, Rolf W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: A new class of potent and selective aldosterone synthase inhibitors</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2015-01-07</date><risdate>2015</risdate><volume>89</volume><spage>597</spage><epage>605</epage><pages>597-605</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols and related compounds were synthesized and evaluated for inhibition of aldosterone synthase (CYP11B2), a potential target for cardiovascular diseases associated with elevated plasma aldosterone levels like congestive heart failure and myocardial fibrosis. Introduction of substituents at the phenylsulfinyl moiety and changes of the substitution pattern at the naphthalene core were examined. Potent compounds were further examined for selectivity versus other important steroidogenic CYP enzymes, i.e. the highly homologous 11β-hydroxylase (CYP11B1), CYP17 and CYP19. The most potent compound (IC50 = 14 nM) discovered was the meta-trifluoromethoxy derivative 11, which also exhibited excellent selectivity toward CYP11B1 (SF = 415), and showed no inhibition of CYP17 and CYP19.
[Display omitted]
•Inhibition of aldosterone synthase is a superior treatment of cardiovascular diseases.•1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols were synthesized and evaluated.•These compounds are potent aldosterone synthase inhibitors (IC50 < 65 nM).•High selectivity over CYP11B1, CYP17 and CYP19 were achieved.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>25462268</pmid><doi>10.1016/j.ejmech.2014.10.027</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols 11β-hydroxylase Aldosterone Aldosterone synthase Animals Cytochrome P-450 CYP11B2 - antagonists & inhibitors Cytochrome P-450 CYP11B2 - metabolism Dose-Response Relationship, Drug Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - classification Enzyme Inhibitors - pharmacology Humans Male Models, Molecular Naphthols - chemical synthesis Naphthols - chemistry Naphthols - pharmacology Rats Rats, Wistar Selectivity Structure-Activity Relationship Sulfoxides - chemical synthesis Sulfoxides - chemistry Sulfoxides - pharmacology |
| title | 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: A new class of potent and selective aldosterone synthase inhibitors |
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