Structure–activity investigation of the inhibition of 3-hydroxypyridin-4-ones on mammalian tyrosine hydroxylase
1 3-Hydroxypyridin-4-ones are currently one of the main candidates for the development of orally active iron chelators. Small bidentate ligands tend to inhibit iron-containing metalloenzymes and therefore can cause undesirable side effects. A range of 3-hydroxypyridin-4-ones with different R 2 subst...
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| Veröffentlicht in: | Biochemical pharmacology 2001-02, Vol.61 (3), p.285-290 |
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| container_title | Biochemical pharmacology |
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| creator | Liu, Zu Dong Lockwood, Michelle Rose, Sarah Theobald, Anthony E Hider, Robert C |
| description | 1
3-Hydroxypyridin-4-ones are currently one of the main candidates for the development of orally active iron chelators. Small bidentate ligands tend to inhibit iron-containing metalloenzymes and therefore can cause undesirable side effects. A range of 3-hydroxypyridin-4-ones with different R
2 substitutents was selected for the investigation of the structure–activity relationship between the chemical nature of the ligand and the inhibition of mammalian tyrosine hydroxylase. Results indicated that lipophilicity was the dominant factor in controlling the ability of this class of chelator to inhibit mammalian tyrosine hydroxylase. Ligands with hydrophilic R
2 substitutents tended to be weak inhibitors. No significant correlation was found in this study between iron-binding affinity, extended R
2 chain length, and enzyme inhibitory activity. In contrast, both the LogP values of the entire molecule and of the R
2 segment correlated well with inhibitory activity. |
| doi_str_mv | 10.1016/S0006-2952(00)00551-7 |
| format | Article |
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3-Hydroxypyridin-4-ones are currently one of the main candidates for the development of orally active iron chelators. Small bidentate ligands tend to inhibit iron-containing metalloenzymes and therefore can cause undesirable side effects. A range of 3-hydroxypyridin-4-ones with different R
2 substitutents was selected for the investigation of the structure–activity relationship between the chemical nature of the ligand and the inhibition of mammalian tyrosine hydroxylase. Results indicated that lipophilicity was the dominant factor in controlling the ability of this class of chelator to inhibit mammalian tyrosine hydroxylase. Ligands with hydrophilic R
2 substitutents tended to be weak inhibitors. No significant correlation was found in this study between iron-binding affinity, extended R
2 chain length, and enzyme inhibitory activity. In contrast, both the LogP values of the entire molecule and of the R
2 segment correlated well with inhibitory activity.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/S0006-2952(00)00551-7</identifier><identifier>PMID: 11172732</identifier><identifier>CODEN: BCPCA6</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Animals ; Biological and medical sciences ; Brain - drug effects ; Brain - enzymology ; Brain - metabolism ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; General pharmacology ; Hydroxypyridinone ; In Vitro Techniques ; Iron Chelating Agents - chemistry ; Iron Chelating Agents - pharmacology ; Iron chelators ; Levodopa - metabolism ; Lipophilicity ; Male ; Medical sciences ; Pharmacology. Drug treatments ; Physicochemical properties. Structure-activity relationships ; Pyridines - chemistry ; Pyridines - pharmacology ; Rats ; Rats, Wistar ; Structure-Activity Relationship ; Tyrosine 3-Monooxygenase - antagonists & inhibitors ; Tyrosine 3-Monooxygenase - metabolism ; Tyrosine hydroxylase</subject><ispartof>Biochemical pharmacology, 2001-02, Vol.61 (3), p.285-290</ispartof><rights>2001 Elsevier Science Inc.</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-ce3e4e63b2c7a41496e1c38a7ff438f010e154347ecbf51f0a0a0064915689f33</citedby><cites>FETCH-LOGICAL-c389t-ce3e4e63b2c7a41496e1c38a7ff438f010e154347ecbf51f0a0a0064915689f33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0006-2952(00)00551-7$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27922,27923,45993</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=870180$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11172732$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Zu Dong</creatorcontrib><creatorcontrib>Lockwood, Michelle</creatorcontrib><creatorcontrib>Rose, Sarah</creatorcontrib><creatorcontrib>Theobald, Anthony E</creatorcontrib><creatorcontrib>Hider, Robert C</creatorcontrib><title>Structure–activity investigation of the inhibition of 3-hydroxypyridin-4-ones on mammalian tyrosine hydroxylase</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>1
3-Hydroxypyridin-4-ones are currently one of the main candidates for the development of orally active iron chelators. Small bidentate ligands tend to inhibit iron-containing metalloenzymes and therefore can cause undesirable side effects. A range of 3-hydroxypyridin-4-ones with different R
2 substitutents was selected for the investigation of the structure–activity relationship between the chemical nature of the ligand and the inhibition of mammalian tyrosine hydroxylase. Results indicated that lipophilicity was the dominant factor in controlling the ability of this class of chelator to inhibit mammalian tyrosine hydroxylase. Ligands with hydrophilic R
2 substitutents tended to be weak inhibitors. No significant correlation was found in this study between iron-binding affinity, extended R
2 chain length, and enzyme inhibitory activity. In contrast, both the LogP values of the entire molecule and of the R
2 segment correlated well with inhibitory activity.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Brain - drug effects</subject><subject>Brain - enzymology</subject><subject>Brain - metabolism</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>General pharmacology</subject><subject>Hydroxypyridinone</subject><subject>In Vitro Techniques</subject><subject>Iron Chelating Agents - chemistry</subject><subject>Iron Chelating Agents - pharmacology</subject><subject>Iron chelators</subject><subject>Levodopa - metabolism</subject><subject>Lipophilicity</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Physicochemical properties. Structure-activity relationships</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Structure-Activity Relationship</subject><subject>Tyrosine 3-Monooxygenase - antagonists & inhibitors</subject><subject>Tyrosine 3-Monooxygenase - metabolism</subject><subject>Tyrosine hydroxylase</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM9u1DAQhy0EokvhEUCRkBAcAjNxYienClX8kypxKJwtrzNmjRJnazsrcuMdeEOeBG83lCPywfJvvrHHH2NPEV4joHhzDQCirLqmegnwCqBpsJT32AZbyXMs2vtsc4ecsUcxfj8eW4EP2RkiykryasNurlOYTZoD_f75S5vkDi4thfMHisl908lNvphskXaUw53bur8JL3dLH6Yfy34Jrne-rMvJUyxyddTjqAenfZGWMEXnqVjZQUd6zB5YPUR6su7n7Ov7d18uP5ZXnz98unx7VRredqk0xKkmwbeVkbrGuhOEuaKltTVvLSAQNjWvJZmtbdCCzgtE3WEj2s5yfs5enO7dh-lmzt9Ro4uGhkF7muaoJAgUEo5gcwJNHjYGsmof3KjDohDU0bW6da2OIhWAunWtZO57tj4wb0fq_3WtcjPwfAV0NHqwQXvj4h3XSsAWMnVxoijLODgKKhpH3lDvApmk-sn9Z5A_VDSduw</recordid><startdate>20010201</startdate><enddate>20010201</enddate><creator>Liu, Zu Dong</creator><creator>Lockwood, Michelle</creator><creator>Rose, Sarah</creator><creator>Theobald, Anthony E</creator><creator>Hider, Robert C</creator><general>Elsevier Inc</general><general>Elsevier Science</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>20010201</creationdate><title>Structure–activity investigation of the inhibition of 3-hydroxypyridin-4-ones on mammalian tyrosine hydroxylase</title><author>Liu, Zu Dong ; Lockwood, Michelle ; Rose, Sarah ; Theobald, Anthony E ; Hider, Robert C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-ce3e4e63b2c7a41496e1c38a7ff438f010e154347ecbf51f0a0a0064915689f33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Brain - drug effects</topic><topic>Brain - enzymology</topic><topic>Brain - metabolism</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>General pharmacology</topic><topic>Hydroxypyridinone</topic><topic>In Vitro Techniques</topic><topic>Iron Chelating Agents - chemistry</topic><topic>Iron Chelating Agents - pharmacology</topic><topic>Iron chelators</topic><topic>Levodopa - metabolism</topic><topic>Lipophilicity</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Physicochemical properties. Structure-activity relationships</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Structure-Activity Relationship</topic><topic>Tyrosine 3-Monooxygenase - antagonists & inhibitors</topic><topic>Tyrosine 3-Monooxygenase - metabolism</topic><topic>Tyrosine hydroxylase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Zu Dong</creatorcontrib><creatorcontrib>Lockwood, Michelle</creatorcontrib><creatorcontrib>Rose, Sarah</creatorcontrib><creatorcontrib>Theobald, Anthony E</creatorcontrib><creatorcontrib>Hider, Robert C</creatorcontrib><collection>Pascal-Francis</collection><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>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Zu Dong</au><au>Lockwood, Michelle</au><au>Rose, Sarah</au><au>Theobald, Anthony E</au><au>Hider, Robert C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure–activity investigation of the inhibition of 3-hydroxypyridin-4-ones on mammalian tyrosine hydroxylase</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>2001-02-01</date><risdate>2001</risdate><volume>61</volume><issue>3</issue><spage>285</spage><epage>290</epage><pages>285-290</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><coden>BCPCA6</coden><abstract>1
3-Hydroxypyridin-4-ones are currently one of the main candidates for the development of orally active iron chelators. Small bidentate ligands tend to inhibit iron-containing metalloenzymes and therefore can cause undesirable side effects. A range of 3-hydroxypyridin-4-ones with different R
2 substitutents was selected for the investigation of the structure–activity relationship between the chemical nature of the ligand and the inhibition of mammalian tyrosine hydroxylase. Results indicated that lipophilicity was the dominant factor in controlling the ability of this class of chelator to inhibit mammalian tyrosine hydroxylase. Ligands with hydrophilic R
2 substitutents tended to be weak inhibitors. No significant correlation was found in this study between iron-binding affinity, extended R
2 chain length, and enzyme inhibitory activity. In contrast, both the LogP values of the entire molecule and of the R
2 segment correlated well with inhibitory activity.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>11172732</pmid><doi>10.1016/S0006-2952(00)00551-7</doi><tpages>6</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences Brain - drug effects Brain - enzymology Brain - metabolism Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology General pharmacology Hydroxypyridinone In Vitro Techniques Iron Chelating Agents - chemistry Iron Chelating Agents - pharmacology Iron chelators Levodopa - metabolism Lipophilicity Male Medical sciences Pharmacology. Drug treatments Physicochemical properties. Structure-activity relationships Pyridines - chemistry Pyridines - pharmacology Rats Rats, Wistar Structure-Activity Relationship Tyrosine 3-Monooxygenase - antagonists & inhibitors Tyrosine 3-Monooxygenase - metabolism Tyrosine hydroxylase |
| title | Structure–activity investigation of the inhibition of 3-hydroxypyridin-4-ones on mammalian tyrosine hydroxylase |
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