Spiroimidazolidinone NPC1L1 inhibitors. Part 2: Structure–activity studies and in vivo efficacy
Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moder...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-12, Vol.20 (23), p.6929-6932 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Howell, Kobporn L. DeVita, Robert J. Garcia-Calvo, Margarita Meurer, Roger D. Lisnock, JeanMarie Bull, Herbert G. McMasters, Daniel R. McCann, Margaret E. Mills, Sander G. |
| description | Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure–activity relationships for binding activity, and resulted in compounds with in vivo efficacy, thereby providing proof-of-concept that non-β-lactams can be effective CAIs.
Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure–activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including
24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-β-lactams can be effective CAIs. |
| doi_str_mv | 10.1016/j.bmcl.2010.09.138 |
| format | Article |
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Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure–activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including
24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-β-lactams can be effective CAIs.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.09.138</identifier><identifier>PMID: 21030254</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Animals ; Anticholesteremic Agents - chemical synthesis ; Anticholesteremic Agents - pharmacology ; Azetidines ; Biological and medical sciences ; Cholesterol-absorption inhibitor ; Ezetimibe ; General and cellular metabolism. Vitamins ; Hypercholesterolemia ; Imidazoles - chemical synthesis ; Imidazoles - chemistry ; Imidazoles - pharmacology ; Intestinal Absorption - drug effects ; Medical sciences ; Membrane Transport Proteins - drug effects ; Mice ; Niemann-Pick C1-Like 1 protein ; Pharmacology. Drug treatments ; Spiro Compounds - chemical synthesis ; Spiro Compounds - pharmacology ; Spiroimidazolidinone ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-12, Vol.20 (23), p.6929-6932</ispartof><rights>2010 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-da79bb9027ee57713e65cf2e7673427b2b5841a7c41b278914130d44c70316db3</citedby><cites>FETCH-LOGICAL-c417t-da79bb9027ee57713e65cf2e7673427b2b5841a7c41b278914130d44c70316db3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2010.09.138$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23428458$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21030254$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Howell, Kobporn L.</creatorcontrib><creatorcontrib>DeVita, Robert J.</creatorcontrib><creatorcontrib>Garcia-Calvo, Margarita</creatorcontrib><creatorcontrib>Meurer, Roger D.</creatorcontrib><creatorcontrib>Lisnock, JeanMarie</creatorcontrib><creatorcontrib>Bull, Herbert G.</creatorcontrib><creatorcontrib>McMasters, Daniel R.</creatorcontrib><creatorcontrib>McCann, Margaret E.</creatorcontrib><creatorcontrib>Mills, Sander G.</creatorcontrib><title>Spiroimidazolidinone NPC1L1 inhibitors. Part 2: Structure–activity studies and in vivo efficacy</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure–activity relationships for binding activity, and resulted in compounds with in vivo efficacy, thereby providing proof-of-concept that non-β-lactams can be effective CAIs.
Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure–activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including
24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-β-lactams can be effective CAIs.</description><subject>Animals</subject><subject>Anticholesteremic Agents - chemical synthesis</subject><subject>Anticholesteremic Agents - pharmacology</subject><subject>Azetidines</subject><subject>Biological and medical sciences</subject><subject>Cholesterol-absorption inhibitor</subject><subject>Ezetimibe</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Hypercholesterolemia</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - pharmacology</subject><subject>Intestinal Absorption - drug effects</subject><subject>Medical sciences</subject><subject>Membrane Transport Proteins - drug effects</subject><subject>Mice</subject><subject>Niemann-Pick C1-Like 1 protein</subject><subject>Pharmacology. Drug treatments</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - pharmacology</subject><subject>Spiroimidazolidinone</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc2KFDEUhYMoTs_oC7iQbMRVlUkqqVSJm6HRUWh0YBTchVRyC29TP22SamhXvoNv6JOYplvd6erC5TuHe88h5AlnJWe8frEtu9ENpWB5wdqSV809suKylkUlmbpPVqytWdG08vMFuYxxyxiXTMqH5EJwVjGh5IrYux2GGUf09ts8oMdpnoC-v13zDac4fcEO0xxiSW9tSFS8pHcpLC4tAX5-_2Fdwj2mA41p8QiR2slnEd3jfqbQ9-isOzwiD3o7RHh8nlfk05vXH9dvi82Hm3fr603hJNep8Fa3XdcyoQGU1ryCWrlegK51JYXuRKcaya3OdCd003LJK-aldJpVvPZddUWen3x3Yf66QExmxOhgGOwE8xJNq6RqmVb8v6Sus6OSusmkOJEuzDEG6M0u4GjDwXBmjh2YrTl2YI4dGNaa3EEWPT3bL90I_o_kd-gZeHYGbHR26IOdHMa_XP63kepo9OrEQY5tjxBMdAiTA48BXDJ-xn_d8QtPd6Sb</recordid><startdate>20101201</startdate><enddate>20101201</enddate><creator>Howell, Kobporn L.</creator><creator>DeVita, Robert J.</creator><creator>Garcia-Calvo, Margarita</creator><creator>Meurer, Roger D.</creator><creator>Lisnock, JeanMarie</creator><creator>Bull, Herbert G.</creator><creator>McMasters, Daniel R.</creator><creator>McCann, Margaret E.</creator><creator>Mills, Sander G.</creator><general>Elsevier Ltd</general><general>Elsevier</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20101201</creationdate><title>Spiroimidazolidinone NPC1L1 inhibitors. Part 2: Structure–activity studies and in vivo efficacy</title><author>Howell, Kobporn L. ; DeVita, Robert J. ; Garcia-Calvo, Margarita ; Meurer, Roger D. ; Lisnock, JeanMarie ; Bull, Herbert G. ; McMasters, Daniel R. ; McCann, Margaret E. ; Mills, Sander G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-da79bb9027ee57713e65cf2e7673427b2b5841a7c41b278914130d44c70316db3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Anticholesteremic Agents - chemical synthesis</topic><topic>Anticholesteremic Agents - pharmacology</topic><topic>Azetidines</topic><topic>Biological and medical sciences</topic><topic>Cholesterol-absorption inhibitor</topic><topic>Ezetimibe</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Hypercholesterolemia</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - pharmacology</topic><topic>Intestinal Absorption - drug effects</topic><topic>Medical sciences</topic><topic>Membrane Transport Proteins - drug effects</topic><topic>Mice</topic><topic>Niemann-Pick C1-Like 1 protein</topic><topic>Pharmacology. 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Part 2: Structure–activity studies and in vivo efficacy</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010-12-01</date><risdate>2010</risdate><volume>20</volume><issue>23</issue><spage>6929</spage><epage>6932</epage><pages>6929-6932</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure–activity relationships for binding activity, and resulted in compounds with in vivo efficacy, thereby providing proof-of-concept that non-β-lactams can be effective CAIs.
Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure–activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including
24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-β-lactams can be effective CAIs.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>21030254</pmid><doi>10.1016/j.bmcl.2010.09.138</doi><tpages>4</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2010-12, Vol.20 (23), p.6929-6932 |
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| subjects | Animals Anticholesteremic Agents - chemical synthesis Anticholesteremic Agents - pharmacology Azetidines Biological and medical sciences Cholesterol-absorption inhibitor Ezetimibe General and cellular metabolism. Vitamins Hypercholesterolemia Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Intestinal Absorption - drug effects Medical sciences Membrane Transport Proteins - drug effects Mice Niemann-Pick C1-Like 1 protein Pharmacology. Drug treatments Spiro Compounds - chemical synthesis Spiro Compounds - pharmacology Spiroimidazolidinone Structure-Activity Relationship |
| title | Spiroimidazolidinone NPC1L1 inhibitors. Part 2: Structure–activity studies and in vivo efficacy |
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