Novel Orally Active Antimalarial Thiazoles
An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC50: 0.08 μM (K1, chloroquine and multidrug resistant strain) and 0.07 μM (NF54, chloroquine sensitive strain)] and microsomal metabolic stability was identified from whole cell screening of a SoftFocus k...
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| Veröffentlicht in: | Journal of medicinal chemistry 2011-11, Vol.54 (21), p.7713-7719 |
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| container_title | Journal of medicinal chemistry |
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| creator | González Cabrera, Diego Douelle, Frederic Feng, Tzu-Shean Nchinda, Aloysius T Younis, Yassir White, Karen L Wu, Quoc Ryan, Eileen Burrows, Jeremy N Waterson, David Witty, Michael J Wittlin, Sergio Charman, Susan A Chibale, Kelly |
| description | An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC50: 0.08 μM (K1, chloroquine and multidrug resistant strain) and 0.07 μM (NF54, chloroquine sensitive strain)] and microsomal metabolic stability was identified from whole cell screening of a SoftFocus kinase library. Compound 3 also exhibited in vivo activity in the P. berghei mouse model at 4 × 50 mg/kg administration via the oral route, showing 99.5% activity and 9 days survival and showed low in vitro cytotoxicity. Pharmacokinetic studies in rats revealed good oral bioavailability (51% at 22 mg/kg) with a moderate rate of absorption, reasonable half-life (t 1/2 3 h), and high volume of distribution with moderately high plasma and blood clearance after IV administration. Toward toxicity profiling, 3 exhibited moderate potential to inhibit CYP1A2 (IC50 = 1.5 μM) and 2D6 (IC50 = 0.4 μM) as well as having a potential hERG liability (IC50 = 3.7 μM). |
| doi_str_mv | 10.1021/jm201108k |
| format | Article |
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Compound 3 also exhibited in vivo activity in the P. berghei mouse model at 4 × 50 mg/kg administration via the oral route, showing 99.5% activity and 9 days survival and showed low in vitro cytotoxicity. Pharmacokinetic studies in rats revealed good oral bioavailability (51% at 22 mg/kg) with a moderate rate of absorption, reasonable half-life (t 1/2 3 h), and high volume of distribution with moderately high plasma and blood clearance after IV administration. Toward toxicity profiling, 3 exhibited moderate potential to inhibit CYP1A2 (IC50 = 1.5 μM) and 2D6 (IC50 = 0.4 μM) as well as having a potential hERG liability (IC50 = 3.7 μM).</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm201108k</identifier><identifier>PMID: 21966980</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Administration, Oral ; Animals ; Antimalarials - chemical synthesis ; Antimalarials - pharmacokinetics ; Antimalarials - pharmacology ; Biological Availability ; Cytochrome P-450 CYP1A2 Inhibitors ; Drug Interactions ; Drug Resistance ; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors ; Humans ; In Vitro Techniques ; Injections, Intravenous ; Malaria - drug therapy ; Male ; Mice ; Microsomes - metabolism ; Parasitic Sensitivity Tests ; Plasmodium berghei ; Plasmodium falciparum - drug effects ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; Thiazoles - chemical synthesis ; Thiazoles - pharmacokinetics ; Thiazoles - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2011-11, Vol.54 (21), p.7713-7719</ispartof><rights>Copyright © 2011 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a314t-7f58a2e460ac750b59fcbb3f6b9b6bb800a79121483b10a826a12c6f9a70ddb83</citedby><cites>FETCH-LOGICAL-a314t-7f58a2e460ac750b59fcbb3f6b9b6bb800a79121483b10a826a12c6f9a70ddb83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm201108k$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm201108k$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21966980$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>González Cabrera, Diego</creatorcontrib><creatorcontrib>Douelle, Frederic</creatorcontrib><creatorcontrib>Feng, Tzu-Shean</creatorcontrib><creatorcontrib>Nchinda, Aloysius T</creatorcontrib><creatorcontrib>Younis, Yassir</creatorcontrib><creatorcontrib>White, Karen L</creatorcontrib><creatorcontrib>Wu, Quoc</creatorcontrib><creatorcontrib>Ryan, Eileen</creatorcontrib><creatorcontrib>Burrows, Jeremy N</creatorcontrib><creatorcontrib>Waterson, David</creatorcontrib><creatorcontrib>Witty, Michael J</creatorcontrib><creatorcontrib>Wittlin, Sergio</creatorcontrib><creatorcontrib>Charman, Susan A</creatorcontrib><creatorcontrib>Chibale, Kelly</creatorcontrib><title>Novel Orally Active Antimalarial Thiazoles</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC50: 0.08 μM (K1, chloroquine and multidrug resistant strain) and 0.07 μM (NF54, chloroquine sensitive strain)] and microsomal metabolic stability was identified from whole cell screening of a SoftFocus kinase library. Compound 3 also exhibited in vivo activity in the P. berghei mouse model at 4 × 50 mg/kg administration via the oral route, showing 99.5% activity and 9 days survival and showed low in vitro cytotoxicity. Pharmacokinetic studies in rats revealed good oral bioavailability (51% at 22 mg/kg) with a moderate rate of absorption, reasonable half-life (t 1/2 3 h), and high volume of distribution with moderately high plasma and blood clearance after IV administration. Toward toxicity profiling, 3 exhibited moderate potential to inhibit CYP1A2 (IC50 = 1.5 μM) and 2D6 (IC50 = 0.4 μM) as well as having a potential hERG liability (IC50 = 3.7 μM).</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antimalarials - chemical synthesis</subject><subject>Antimalarials - pharmacokinetics</subject><subject>Antimalarials - pharmacology</subject><subject>Biological Availability</subject><subject>Cytochrome P-450 CYP1A2 Inhibitors</subject><subject>Drug Interactions</subject><subject>Drug Resistance</subject><subject>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Injections, Intravenous</subject><subject>Malaria - drug therapy</subject><subject>Male</subject><subject>Mice</subject><subject>Microsomes - metabolism</subject><subject>Parasitic Sensitivity Tests</subject><subject>Plasmodium berghei</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - pharmacokinetics</subject><subject>Thiazoles - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptj81Kw0AURgdRbK0ufAHJxoVC9N47yWSyLMU_KHZT1-FOOsHEaVNm2kL79EaiXbn6NoePc4S4RnhAIHxslgSIoL9OxBBTgjjRkJyKIQBRTIrkQFyE0ACARJLnYkCYK5VrGIr793ZnXTTz7Nw-Gpebemej8WpTL9mxr9lF88-aD62z4VKcVeyCvfrdkfh4fppPXuPp7OVtMp7GLDHZxFmVaiabKOAyS8GkeVUaIytlcqOM0QCc5UiYaGkQWJNipFJVOWewWBgtR-Ku_y19G4K3VbH2nY7fFwjFT29x7O3Ym55db83SLo7kX2AH3PYAl6Fo2q1fder_HH0DxOFa4w</recordid><startdate>20111110</startdate><enddate>20111110</enddate><creator>González Cabrera, Diego</creator><creator>Douelle, Frederic</creator><creator>Feng, Tzu-Shean</creator><creator>Nchinda, Aloysius T</creator><creator>Younis, Yassir</creator><creator>White, Karen L</creator><creator>Wu, Quoc</creator><creator>Ryan, Eileen</creator><creator>Burrows, Jeremy N</creator><creator>Waterson, David</creator><creator>Witty, Michael J</creator><creator>Wittlin, Sergio</creator><creator>Charman, Susan A</creator><creator>Chibale, Kelly</creator><general>American Chemical Society</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></search><sort><creationdate>20111110</creationdate><title>Novel Orally Active Antimalarial Thiazoles</title><author>González Cabrera, Diego ; Douelle, Frederic ; Feng, Tzu-Shean ; Nchinda, Aloysius T ; Younis, Yassir ; White, Karen L ; Wu, Quoc ; Ryan, Eileen ; Burrows, Jeremy N ; Waterson, David ; Witty, Michael J ; Wittlin, Sergio ; Charman, Susan A ; Chibale, Kelly</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a314t-7f58a2e460ac750b59fcbb3f6b9b6bb800a79121483b10a826a12c6f9a70ddb83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antimalarials - chemical synthesis</topic><topic>Antimalarials - pharmacokinetics</topic><topic>Antimalarials - pharmacology</topic><topic>Biological Availability</topic><topic>Cytochrome P-450 CYP1A2 Inhibitors</topic><topic>Drug Interactions</topic><topic>Drug Resistance</topic><topic>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Injections, Intravenous</topic><topic>Malaria - drug therapy</topic><topic>Male</topic><topic>Mice</topic><topic>Microsomes - metabolism</topic><topic>Parasitic Sensitivity Tests</topic><topic>Plasmodium berghei</topic><topic>Plasmodium falciparum - drug effects</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - chemical synthesis</topic><topic>Thiazoles - pharmacokinetics</topic><topic>Thiazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>González Cabrera, Diego</creatorcontrib><creatorcontrib>Douelle, Frederic</creatorcontrib><creatorcontrib>Feng, Tzu-Shean</creatorcontrib><creatorcontrib>Nchinda, Aloysius T</creatorcontrib><creatorcontrib>Younis, Yassir</creatorcontrib><creatorcontrib>White, Karen L</creatorcontrib><creatorcontrib>Wu, Quoc</creatorcontrib><creatorcontrib>Ryan, Eileen</creatorcontrib><creatorcontrib>Burrows, Jeremy N</creatorcontrib><creatorcontrib>Waterson, David</creatorcontrib><creatorcontrib>Witty, Michael J</creatorcontrib><creatorcontrib>Wittlin, Sergio</creatorcontrib><creatorcontrib>Charman, Susan A</creatorcontrib><creatorcontrib>Chibale, Kelly</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>González Cabrera, Diego</au><au>Douelle, Frederic</au><au>Feng, Tzu-Shean</au><au>Nchinda, Aloysius T</au><au>Younis, Yassir</au><au>White, Karen L</au><au>Wu, Quoc</au><au>Ryan, Eileen</au><au>Burrows, Jeremy N</au><au>Waterson, David</au><au>Witty, Michael J</au><au>Wittlin, Sergio</au><au>Charman, Susan A</au><au>Chibale, Kelly</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel Orally Active Antimalarial Thiazoles</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2011-11-10</date><risdate>2011</risdate><volume>54</volume><issue>21</issue><spage>7713</spage><epage>7719</epage><pages>7713-7719</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC50: 0.08 μM (K1, chloroquine and multidrug resistant strain) and 0.07 μM (NF54, chloroquine sensitive strain)] and microsomal metabolic stability was identified from whole cell screening of a SoftFocus kinase library. Compound 3 also exhibited in vivo activity in the P. berghei mouse model at 4 × 50 mg/kg administration via the oral route, showing 99.5% activity and 9 days survival and showed low in vitro cytotoxicity. Pharmacokinetic studies in rats revealed good oral bioavailability (51% at 22 mg/kg) with a moderate rate of absorption, reasonable half-life (t 1/2 3 h), and high volume of distribution with moderately high plasma and blood clearance after IV administration. 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| ispartof | Journal of medicinal chemistry, 2011-11, Vol.54 (21), p.7713-7719 |
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| source | MEDLINE; ACS Journals: American Chemical Society Web Editions |
| subjects | Administration, Oral Animals Antimalarials - chemical synthesis Antimalarials - pharmacokinetics Antimalarials - pharmacology Biological Availability Cytochrome P-450 CYP1A2 Inhibitors Drug Interactions Drug Resistance Ether-A-Go-Go Potassium Channels - antagonists & inhibitors Humans In Vitro Techniques Injections, Intravenous Malaria - drug therapy Male Mice Microsomes - metabolism Parasitic Sensitivity Tests Plasmodium berghei Plasmodium falciparum - drug effects Rats Rats, Sprague-Dawley Structure-Activity Relationship Thiazoles - chemical synthesis Thiazoles - pharmacokinetics Thiazoles - pharmacology |
| title | Novel Orally Active Antimalarial Thiazoles |
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