SC83288 is a clinical development candidate for the treatment of severe malaria
Identifieur interne : 000784 ( Pmc/Curation ); précédent : 000783; suivant : 000785SC83288 is a clinical development candidate for the treatment of severe malaria
Auteurs : Stefano Pegoraro [Allemagne] ; Maëlle Duffey [Allemagne] ; Thomas D. Otto [Royaume-Uni] ; Yulin Wang [Allemagne] ; Roman Rösemann [Allemagne] ; Roland Baumgartner [Allemagne] ; Stefanie K. Fehler [Allemagne] ; Leonardo Lucantoni [Australie] ; Vicky M. Avery [Australie] ; Alicia Moreno-Sabater [France] ; Dominique Mazier [France] ; Henri J. Vial [France] ; Stefan Strobl [Allemagne] ; Cecilia P. Sanchez [Allemagne] ; Michael Lanzer [Allemagne]Source :
- Nature Communications [ 2041-1723 ] ; 2017.
Abstract
Severe malaria is a life-threatening complication of an infection with the protozoan parasite
Url:
DOI: 10.1038/ncomms14193
PubMed: 28139658
PubMed Central: 5290327
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">SC83288 is a clinical development candidate for the treatment of severe malaria</title><author><name sortKey="Pegoraro, Stefano" sort="Pegoraro, Stefano" uniqKey="Pegoraro S" first="Stefano" last="Pegoraro">Stefano Pegoraro</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>4SC AG, Am Klopferspitz 19a</institution>, 82152 Martinsried,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Duffey, Maelle" sort="Duffey, Maelle" uniqKey="Duffey M" first="Maëlle" last="Duffey">Maëlle Duffey</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg</institution>, Im Neuenheimer Feld 324, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>German Center for Infection Research (DZIF), partner site Heidelberg</institution>, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Otto, Thomas D" sort="Otto, Thomas D" uniqKey="Otto T" first="Thomas D" last="Otto">Thomas D. Otto</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Parasite Genomics, Wellcome Trust Sanger Institute, Wellcome Genome Campus</institution>, Hinxton CB10 1SA,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Yulin" sort="Wang, Yulin" uniqKey="Wang Y" first="Yulin" last="Wang">Yulin Wang</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg</institution>, Im Neuenheimer Feld 324, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>German Center for Infection Research (DZIF), partner site Heidelberg</institution>, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Rosemann, Roman" sort="Rosemann, Roman" uniqKey="Rosemann R" first="Roman" last="Rösemann">Roman Rösemann</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>4SC Discovery GmbH, Am Klopferspitz 19a</institution>, 82152 Martinsried,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Baumgartner, Roland" sort="Baumgartner, Roland" uniqKey="Baumgartner R" first="Roland" last="Baumgartner">Roland Baumgartner</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>4SC AG, Am Klopferspitz 19a</institution>, 82152 Martinsried,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fehler, Stefanie K" sort="Fehler, Stefanie K" uniqKey="Fehler S" first="Stefanie K" last="Fehler">Stefanie K. Fehler</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>4SC AG, Am Klopferspitz 19a</institution>, 82152 Martinsried,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg</institution>, Im Neuenheimer Feld 324, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>German Center for Infection Research (DZIF), partner site Heidelberg</institution>, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lucantoni, Leonardo" sort="Lucantoni, Leonardo" uniqKey="Lucantoni L" first="Leonardo" last="Lucantoni">Leonardo Lucantoni</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Eskitis Institute for Drug Discovery, Griffith University, Don Young</institution>, Nathan Queensland 4111,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M" last="Avery">Vicky M. Avery</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Eskitis Institute for Drug Discovery, Griffith University, Don Young</institution>, Nathan Queensland 4111,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Moreno Sabater, Alicia" sort="Moreno Sabater, Alicia" uniqKey="Moreno Sabater A" first="Alicia" last="Moreno-Sabater">Alicia Moreno-Sabater</name><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), 91 Bd de l'hôpital</institution>, F-75013 Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a8"><institution>AP-HP, Hôpital St Antoine, Service de Parasitologie-Mycologie</institution>, F-75012 Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mazier, Dominique" sort="Mazier, Dominique" uniqKey="Mazier D" first="Dominique" last="Mazier">Dominique Mazier</name><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), 91 Bd de l'hôpital</institution>, F-75013 Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a9"><institution>AP-HP, Groupe hospitalier La Pitié-Salpêtrière, Service de Parasitologie-Mycologie</institution>, F-75013 Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Vial, Henri J" sort="Vial, Henri J" uniqKey="Vial H" first="Henri J" last="Vial">Henri J. Vial</name><affiliation wicri:level="1"><nlm:aff id="a10"><institution>Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier II</institution>, cc107, Place Eugène Bataillon, 34095 Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Strobl, Stefan" sort="Strobl, Stefan" uniqKey="Strobl S" first="Stefan" last="Strobl">Stefan Strobl</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>4SC Discovery GmbH, Am Klopferspitz 19a</institution>, 82152 Martinsried,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sanchez, Cecilia P" sort="Sanchez, Cecilia P" uniqKey="Sanchez C" first="Cecilia P" last="Sanchez">Cecilia P. Sanchez</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg</institution>, Im Neuenheimer Feld 324, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>German Center for Infection Research (DZIF), partner site Heidelberg</institution>, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lanzer, Michael" sort="Lanzer, Michael" uniqKey="Lanzer M" first="Michael" last="Lanzer">Michael Lanzer</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg</institution>, Im Neuenheimer Feld 324, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>German Center for Infection Research (DZIF), partner site Heidelberg</institution>, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28139658</idno><idno type="pmc">5290327</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290327</idno><idno type="RBID">PMC:5290327</idno><idno type="doi">10.1038/ncomms14193</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000785</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000785</idno><idno type="wicri:Area/Pmc/Curation">000784</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000784</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">SC83288 is a clinical development candidate for the treatment of severe malaria</title><author><name sortKey="Pegoraro, Stefano" sort="Pegoraro, Stefano" uniqKey="Pegoraro S" first="Stefano" last="Pegoraro">Stefano Pegoraro</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>4SC AG, Am Klopferspitz 19a</institution>, 82152 Martinsried,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Duffey, Maelle" sort="Duffey, Maelle" uniqKey="Duffey M" first="Maëlle" last="Duffey">Maëlle Duffey</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg</institution>, Im Neuenheimer Feld 324, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>German Center for Infection Research (DZIF), partner site Heidelberg</institution>, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Otto, Thomas D" sort="Otto, Thomas D" uniqKey="Otto T" first="Thomas D" last="Otto">Thomas D. Otto</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Parasite Genomics, Wellcome Trust Sanger Institute, Wellcome Genome Campus</institution>, Hinxton CB10 1SA,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Yulin" sort="Wang, Yulin" uniqKey="Wang Y" first="Yulin" last="Wang">Yulin Wang</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg</institution>, Im Neuenheimer Feld 324, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>German Center for Infection Research (DZIF), partner site Heidelberg</institution>, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Rosemann, Roman" sort="Rosemann, Roman" uniqKey="Rosemann R" first="Roman" last="Rösemann">Roman Rösemann</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>4SC Discovery GmbH, Am Klopferspitz 19a</institution>, 82152 Martinsried,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Baumgartner, Roland" sort="Baumgartner, Roland" uniqKey="Baumgartner R" first="Roland" last="Baumgartner">Roland Baumgartner</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>4SC AG, Am Klopferspitz 19a</institution>, 82152 Martinsried,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fehler, Stefanie K" sort="Fehler, Stefanie K" uniqKey="Fehler S" first="Stefanie K" last="Fehler">Stefanie K. Fehler</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>4SC AG, Am Klopferspitz 19a</institution>, 82152 Martinsried,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg</institution>, Im Neuenheimer Feld 324, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>German Center for Infection Research (DZIF), partner site Heidelberg</institution>, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lucantoni, Leonardo" sort="Lucantoni, Leonardo" uniqKey="Lucantoni L" first="Leonardo" last="Lucantoni">Leonardo Lucantoni</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Eskitis Institute for Drug Discovery, Griffith University, Don Young</institution>, Nathan Queensland 4111,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M" last="Avery">Vicky M. Avery</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Eskitis Institute for Drug Discovery, Griffith University, Don Young</institution>, Nathan Queensland 4111,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Moreno Sabater, Alicia" sort="Moreno Sabater, Alicia" uniqKey="Moreno Sabater A" first="Alicia" last="Moreno-Sabater">Alicia Moreno-Sabater</name><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), 91 Bd de l'hôpital</institution>, F-75013 Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a8"><institution>AP-HP, Hôpital St Antoine, Service de Parasitologie-Mycologie</institution>, F-75012 Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mazier, Dominique" sort="Mazier, Dominique" uniqKey="Mazier D" first="Dominique" last="Mazier">Dominique Mazier</name><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), 91 Bd de l'hôpital</institution>, F-75013 Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a9"><institution>AP-HP, Groupe hospitalier La Pitié-Salpêtrière, Service de Parasitologie-Mycologie</institution>, F-75013 Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Vial, Henri J" sort="Vial, Henri J" uniqKey="Vial H" first="Henri J" last="Vial">Henri J. Vial</name><affiliation wicri:level="1"><nlm:aff id="a10"><institution>Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier II</institution>, cc107, Place Eugène Bataillon, 34095 Montpellier,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Strobl, Stefan" sort="Strobl, Stefan" uniqKey="Strobl S" first="Stefan" last="Strobl">Stefan Strobl</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>4SC Discovery GmbH, Am Klopferspitz 19a</institution>, 82152 Martinsried,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sanchez, Cecilia P" sort="Sanchez, Cecilia P" uniqKey="Sanchez C" first="Cecilia P" last="Sanchez">Cecilia P. Sanchez</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg</institution>, Im Neuenheimer Feld 324, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>German Center for Infection Research (DZIF), partner site Heidelberg</institution>, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lanzer, Michael" sort="Lanzer, Michael" uniqKey="Lanzer M" first="Michael" last="Lanzer">Michael Lanzer</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg</institution>, Im Neuenheimer Feld 324, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>German Center for Infection Research (DZIF), partner site Heidelberg</institution>, 69120 Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Severe malaria is a life-threatening complication of an infection with the protozoan parasite <italic>Plasmodium falciparum</italic>, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a <italic>P. falciparum</italic> infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca<sup>2+</sup> transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Dondorp, A M" uniqKey="Dondorp A">A. M. Dondorp</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ashley, E A" uniqKey="Ashley E">E. A. Ashley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jimenez Diaz, M B" uniqKey="Jimenez Diaz M">M. B. Jimenez-Diaz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Charman, S A" uniqKey="Charman S">S. A. Charman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vial, H J" uniqKey="Vial H">H. J. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28139658</article-id><article-id pub-id-type="pmc">5290327</article-id><article-id pub-id-type="pii">ncomms14193</article-id><article-id pub-id-type="doi">10.1038/ncomms14193</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>SC83288 is a clinical development candidate for the treatment of severe malaria</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Pegoraro</surname><given-names>Stefano</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Duffey</surname><given-names>Maëlle</given-names></name><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Otto</surname><given-names>Thomas D</given-names></name><xref ref-type="aff" rid="a4">4</xref><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-1246-7404</contrib-id></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Yulin</given-names></name><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a3">3</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Rösemann</surname><given-names>Roman</given-names></name><xref ref-type="aff" rid="a5">5</xref></contrib><contrib contrib-type="author"><name><surname>Baumgartner</surname><given-names>Roland</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Fehler</surname><given-names>Stefanie K</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Lucantoni</surname><given-names>Leonardo</given-names></name><xref ref-type="aff" rid="a6">6</xref></contrib><contrib contrib-type="author"><name><surname>Avery</surname><given-names>Vicky M</given-names></name><xref ref-type="aff" rid="a6">6</xref><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-4914-2299</contrib-id></contrib><contrib contrib-type="author"><name><surname>Moreno-Sabater</surname><given-names>Alicia</given-names></name><xref ref-type="aff" rid="a7">7</xref><xref ref-type="aff" rid="a8">8</xref></contrib><contrib contrib-type="author"><name><surname>Mazier</surname><given-names>Dominique</given-names></name><xref ref-type="aff" rid="a7">7</xref><xref ref-type="aff" rid="a9">9</xref></contrib><contrib contrib-type="author"><name><surname>Vial</surname><given-names>Henri J</given-names></name><xref ref-type="aff" rid="a10">10</xref></contrib><contrib contrib-type="author"><name><surname>Strobl</surname><given-names>Stefan</given-names></name><xref ref-type="aff" rid="a5">5</xref></contrib><contrib contrib-type="author"><name><surname>Sanchez</surname><given-names>Cecilia P</given-names></name><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Lanzer</surname><given-names>Michael</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a3">3</xref><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-0220-6526</contrib-id></contrib><aff id="a1"><label>1</label><institution>4SC AG, Am Klopferspitz 19a</institution>, 82152 Martinsried,<country>Germany</country></aff><aff id="a2"><label>2</label><institution>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg</institution>, Im Neuenheimer Feld 324, 69120 Heidelberg,<country>Germany</country></aff><aff id="a3"><label>3</label><institution>German Center for Infection Research (DZIF), partner site Heidelberg</institution>, 69120 Heidelberg,<country>Germany</country></aff><aff id="a4"><label>4</label><institution>Parasite Genomics, Wellcome Trust Sanger Institute, Wellcome Genome Campus</institution>, Hinxton CB10 1SA,<country>UK</country></aff><aff id="a5"><label>5</label><institution>4SC Discovery GmbH, Am Klopferspitz 19a</institution>, 82152 Martinsried,<country>Germany</country></aff><aff id="a6"><label>6</label><institution>Eskitis Institute for Drug Discovery, Griffith University, Don Young</institution>, Nathan Queensland 4111,<country>Australia</country></aff><aff id="a7"><label>7</label><institution>Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), 91 Bd de l'hôpital</institution>, F-75013 Paris,<country>France</country></aff><aff id="a8"><label>8</label><institution>AP-HP, Hôpital St Antoine, Service de Parasitologie-Mycologie</institution>, F-75012 Paris,<country>France</country></aff><aff id="a9"><label>9</label><institution>AP-HP, Groupe hospitalier La Pitié-Salpêtrière, Service de Parasitologie-Mycologie</institution>, F-75013 Paris,<country>France</country></aff><aff id="a10"><label>10</label><institution>Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier II</institution>, cc107, Place Eugène Bataillon, 34095 Montpellier,<country>France</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>stefano.pegoraro@4sc.com</email></corresp><corresp id="c2"><label>b</label><email>michael.lanzer@med.uni-heidelberg.de</email></corresp><fn id="n1"><label>*</label><p>Present address: Department of Parasitology, College of Basic Medical Sciences, Dalian Medical University, 9 South Lvshun Road Western Section, Dalian, Liaoning 116044, China</p></fn></author-notes><pub-date pub-type="epub"><day>31</day><month>01</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>8</volume><elocation-id>14193</elocation-id><history><date date-type="received"><day>10</day><month>06</month><year>2016</year></date><date date-type="accepted"><day>07</day><month>12</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2017, The Author(s)</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>The Author(s)</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>Severe malaria is a life-threatening complication of an infection with the protozoan parasite <italic>Plasmodium falciparum</italic>, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a <italic>P. falciparum</italic> infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca<sup>2+</sup> transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria.</p></abstract><abstract abstract-type="web-summary"><p>Severe malaria is a life-threatening infection with limited treatment options. Here, using a medicinal chemistry approach starting from amicarbalide, Pegoraro <italic>et al</italic>. identify a compound that, when delivered intravenously, can cure <italic>Plasmodium falciparum</italic> infection in a humanized mouse model.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>Structures and <italic>in vitro</italic> activities of hit and lead compounds.</title><p>The names of the compounds, their half maximal inhibitory concentrations (IC<sub>50</sub>), and their molecular masses are indicated.</p></caption><graphic xlink:href="ncomms14193-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>Structure-activity relationship (SAR) analysis.</title><p>(<bold>a</bold>) Antiplasmodial activity of 172 chronologically ordered amicarbalide derivatives against the <italic>P. falciparum</italic> strain Dd2. Substitutions on the West-side amidine group (grey), the benzamidine urea linker (green) and the East-side sulfonamide group (dark blue and red) are indicated. The two compounds SC81458 and SC83288 are highlighted. (<bold>b</bold>) Summary of the SAR analysis. Colour code as above.</p></caption><graphic xlink:href="ncomms14193-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>Susceptibility of the <italic>P. falciparum</italic> strain Dd2 to SC81458 and SC83288.</title><p>(<bold>a</bold>) Growth inhibition by SC81458 (closed circles) and SC83288 (open circles) in a standard cell proliferation assay with an exposure time of 72 h. (<bold>b</bold>,<bold>c</bold>) Growth inhibition by SC81458 (<bold>b</bold>) and SC83288 (<bold>c</bold>) against rings (R, closed circles), trophozoites (T, open circles) and schizonts (S, closed inverted triangles) after an exposure time of 6 h. The mean±s.e.m. are shown for at least six independent replicates.</p></caption><graphic xlink:href="ncomms14193-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title><italic>In vitro</italic> killing kinetic profile of SC81458 and SC83288.</title><p>(<bold>a</bold>) Concentration and exposure time-dependent clearance of a 0.5% parasitemia of trophozoites. The following drugs were investigated: artemisinin (ART, closed inversed triangles), SC81458 (closed circles) and SC83288 (open circles). (<bold>b</bold>) The graph shows the change in the number of viable parasites over time after exposure to ART (closed inversed triangles; 19 nM), atovaquone (ATO, open triangles; 10 nM), SC81458 (closed circles; 80 nM), and SC83288 (open circles; 30 nM) at a concentration corresponding to 10 times their respective IC<sub>50</sub> values. The mean±s.e.m. are shown for at least four independent replicates.</p></caption><graphic xlink:href="ncomms14193-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>Stability of SC81458 and SC83288 in liver microsomes.</title><p>Suggested metabolic reactions and biotransformation sites of SC81458 (<bold>a</bold>) and SC83288 (<bold>b</bold>). Further detail is provided in <xref ref-type="supplementary-material" rid="S1">Supplementary Figs 5 and 6</xref>.</p></caption><graphic xlink:href="ncomms14193-f5"></graphic></fig><fig id="f6"><label>Figure 6</label><caption><title><italic>In vivo</italic> efficacy of SC81458 and SC83288 in <italic>P. falciparum</italic>-infected humanized NSG mice.</title><p>NSG mice engrafted with human erythrocytes were infected with the <italic>P. falciparum</italic> strains 3D7 (<bold>a</bold>,<bold>c</bold>) or W2 (<bold>b</bold>,<bold>d</bold>). The compounds SC81458 (<bold>a</bold>,<bold>b</bold>) or SC83288 (<bold>c</bold>,<bold>d</bold>) were administered i.p. once per day over 4 days starting on day 7 post infection. Parasitemia was assessed each day from day 2 post infection up to 12 days. The mean±s.e.m. of four mice in each treatment group are shown.</p></caption><graphic xlink:href="ncomms14193-f6"></graphic></fig><fig id="f7"><label>Figure 7</label><caption><title>Pharmacokinetic profiles of SC81458 and SC83288.</title><p>(<bold>a</bold>,<bold>b</bold>) Mean plasma concentration of SC81458 (<bold>a</bold>) and SC83288 (<bold>b</bold>) over time following i.p. administration of the indicated doses in mice. (<bold>c</bold>) Mean plasma concentration of SC83288 over time following i.v. administration of 2 mg kg<sup>−1</sup> in monkeys (closed circles), mice (open circles), and rats (closed inverted triangles) and of 1.7 mg kg<sup>−1</sup> in dogs (open triangles). For comparative reasons, the SC83288 AUC of the i.p. 10 mg kg<sup>−1</sup> treatment group in mice is indicated in grey. The dotted lines show the lower limit of quantification (LLoQ). The mean±s.e.m. are shown for at least three animals. Data were examined using a non-compartment analysis (NCA) and relevant PK parameters are compiled in <xref ref-type="table" rid="t2">Table 2</xref>. (<bold>d</bold>) Four species allometric scaling of the plasma clearance rate (CL) of SC83288, according to Ring <italic>et al</italic>.<xref ref-type="bibr" rid="b30">30</xref>. The CL values were corrected for the maximum life potential (MLP). The function <italic>y</italic>=<italic>ax</italic><sup><italic>b</italic></sup> was fitted to the data points, yielding values for <italic>a</italic> of 9.47 and <italic>b</italic> of 1.17 (<italic>R</italic><sup>2</sup>=0.997). Extrapolation of the fit provided estimates of the human blood clearance rate (red circle).</p></caption><graphic xlink:href="ncomms14193-f7"></graphic></fig><fig id="f8"><label>Figure 8</label><caption><title><italic>In vitro</italic> generation of SC81458 and SC83288-resistant <italic>P. falciparum</italic> clones.</title><p>(<bold>a</bold>,<bold>b</bold>) ∼10<sup>10</sup> infected erythrocytes were treated with increasing concentration of SC81458 (<bold>a</bold>) or SC83288 (<bold>b</bold>) and the decrease in drug susceptibility was monitored over time. Clones obtained at different time points during selection are indicated. The means±s.e.m. of at least three independent determinations are shown. (<bold>c</bold>) Cross resistance between SC81458- and SC83288-selected clones. (<bold>d</bold>) Identified single-nucleotide polymorphisms (SNPs) and gene amplifications in the genome of resistant clones. The arrows point in the direction of increased selective pressure. SNPs and gene amplifications associated with resistance to SC compounds are highlighted in blue. This includes PfMDR2 (position 1237), a putative ATP-dependent RNA helicase DBP9 (position 533) and PfATP6 (position 322 and 325), as well as an amplification of the PfATP6 locus.</p></caption><graphic xlink:href="ncomms14193-f8"></graphic></fig><table-wrap position="float" id="t1"><label>Table 1</label><caption><title>Relevant activity parameters of SC81458 and SC83288.</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="center"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th><th align="center" valign="top" charoff="50"><bold>SC81458</bold></th><th align="center" valign="top" charoff="50"><bold>SC83288</bold></th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50">IC<sub>50</sub>, IC<sub>90</sub>, IC<sub>99</sub> (nM)</td><td align="center" valign="top" charoff="50">8, 18, 50</td><td align="center" valign="top" charoff="50">3, 8, 20</td></tr><tr><td align="left" valign="top" charoff="50"><italic>In vitro</italic> PCT<sub>99.9%</sub> (h)</td><td align="center" valign="top" charoff="50">37±4 (4)</td><td align="center" valign="top" charoff="50">51±6 (4)</td></tr><tr><td align="left" valign="top" charoff="50"><italic>In vitro</italic> logPRR</td><td align="center" valign="top" charoff="50">3.4±0.4 (4)</td><td align="center" valign="top" charoff="50">3.0±0.5 (4)</td></tr><tr><td align="left" valign="top" charoff="50"><italic>In vitro</italic> lag phase (h)</td><td align="center" valign="top" charoff="50"><5</td><td align="center" valign="top" charoff="50"><5</td></tr><tr><td align="left" valign="top" charoff="50"><italic>In vivo</italic> PCT<sub>99.9%</sub> (h)<xref ref-type="fn" rid="t1-fn3">*</xref></td><td align="center" valign="top" charoff="50"><48</td><td align="center" valign="top" charoff="50">48</td></tr><tr><td align="left" valign="top" charoff="50"><italic>In viv</italic>o logPRR<xref ref-type="fn" rid="t1-fn3">*</xref></td><td align="center" valign="top" charoff="50">5.3 (W2), 3.2 (3D7)</td><td align="center" valign="top" charoff="50">3.0</td></tr></tbody></table><table-wrap-foot><fn id="t1-fn1"><p>IC<sub>50/90/99</sub>, inhibitory concentration of 50, 90 or 99% of the maximal effect; PCT<sub>99.9%</sub>, clearance time of 99.9% of the original parasite population; PRR, parasite reduction ratio.</p></fn><fn id="t1-fn2"><p>For the <italic>in vitro</italic> PCT<sub>99.9%</sub> and the <italic>in vitro</italic> logPRR the means±s.e. of the means of (<italic>n</italic>) independent determinations are shown.</p></fn><fn id="t1-fn3"><p><sup>*</sup>Obtained in the <italic>P. falciparum</italic>-infected humanized NSG mouse model system.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t2"><label>Table 2</label><caption><title>Pharmacokinetic parameters of SC81458 and SC83288.</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><bold>Compound</bold></th><th colspan="4" align="center" valign="top" charoff="50"><bold>SC81458</bold><hr></hr></th><th colspan="4" align="center" valign="top" charoff="50"><bold>SC83288</bold><hr></hr></th></tr><tr><th align="left" valign="top" charoff="50"><bold>Application</bold></th><th colspan="4" align="center" valign="top" charoff="50"><bold>i.p.</bold><hr></hr></th><th colspan="4" align="center" valign="top" charoff="50"><bold>i.v.</bold><hr></hr></th></tr><tr><th align="left" valign="top" charoff="50"><bold>Species</bold></th><th colspan="4" align="center" valign="top" charoff="50"><bold>Mouse</bold></th><th align="center" valign="top" charoff="50"><bold>Mouse</bold></th><th align="center" valign="top" charoff="50"><bold>Rat</bold></th><th align="center" valign="top" charoff="50"><bold>Dog</bold></th><th align="center" valign="top" charoff="50"><bold>Cynomolgus</bold></th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50">Dose (mg kg<sup>−1</sup>)</td><td align="center" valign="top" charoff="50">20</td><td align="center" valign="top" charoff="50">2.5</td><td align="center" valign="top" charoff="50">5</td><td align="center" valign="top" charoff="50">10</td><td align="center" valign="top" charoff="50">2</td><td align="center" valign="top" charoff="50">2</td><td align="center" valign="top" charoff="50">1.7</td><td align="center" valign="top" charoff="50">2</td></tr><tr><td align="left" valign="top" charoff="50">AUC<sub>0-inf</sub> (ng h ml<sup>−1</sup>)</td><td align="center" valign="top" charoff="50">4,342</td><td align="center" valign="top" charoff="50">646</td><td align="center" valign="top" charoff="50">1,089</td><td align="center" valign="top" charoff="50">2,019</td><td align="center" valign="top" charoff="50">891</td><td align="center" valign="top" charoff="50">1,419</td><td align="center" valign="top" charoff="50">2,262</td><td align="center" valign="top" charoff="50">4,253</td></tr><tr><td align="left" valign="top" charoff="50"><italic>C</italic><sub>0</sub> (ng ml<sup>−1</sup>)</td><td align="center" valign="top" charoff="50">0</td><td align="center" valign="top" charoff="50">0</td><td align="center" valign="top" charoff="50">0</td><td align="center" valign="top" charoff="50">0</td><td align="center" valign="top" charoff="50">3,644</td><td align="center" valign="top" charoff="50">4,375</td><td align="center" valign="top" charoff="50">5,579</td><td align="center" valign="top" charoff="50">7,338</td></tr><tr><td align="left" valign="top" charoff="50"><italic>C</italic><sub>max</sub> (ng ml<sup>−1</sup>)</td><td align="center" valign="top" charoff="50">7,384</td><td align="center" valign="top" charoff="50">610</td><td align="center" valign="top" charoff="50">1,338</td><td align="center" valign="top" charoff="50">1,711</td><td align="center" valign="top" charoff="50">2,560</td><td align="center" valign="top" charoff="50">3,283</td><td align="center" valign="top" charoff="50">4,564</td><td align="center" valign="top" charoff="50">6,569</td></tr><tr><td align="left" valign="top" charoff="50"><italic>t</italic><sub>max</sub> (min)</td><td align="center" valign="top" charoff="50">30</td><td align="center" valign="top" charoff="50">5</td><td align="center" valign="top" charoff="50">5</td><td align="center" valign="top" charoff="50">30</td><td align="center" valign="top" charoff="50">5</td><td align="center" valign="top" charoff="50">5</td><td align="center" valign="top" charoff="50">5</td><td align="center" valign="top" charoff="50">5</td></tr><tr><td align="left" valign="top" charoff="50"><italic>t</italic><sub>1/2 initial</sub> (min)</td><td align="center" valign="top" charoff="50">NC</td><td align="center" valign="top" charoff="50">NC</td><td align="center" valign="top" charoff="50">NC</td><td align="center" valign="top" charoff="50">NC</td><td align="center" valign="top" charoff="50">9</td><td align="center" valign="top" charoff="50">9</td><td align="center" valign="top" charoff="50">12</td><td align="center" valign="top" charoff="50">16</td></tr><tr><td align="left" valign="top" charoff="50"><italic>t</italic><sub>1/2 terminal</sub> (min)</td><td align="center" valign="top" charoff="50">860</td><td align="center" valign="top" charoff="50">100</td><td align="center" valign="top" charoff="50">73</td><td align="center" valign="top" charoff="50">46</td><td align="center" valign="top" charoff="50">43</td><td align="center" valign="top" charoff="50">625</td><td align="center" valign="top" charoff="50">90</td><td align="center" valign="top" charoff="50">320</td></tr><tr><td align="left" valign="top" charoff="50"><italic>t</italic><sub>1/2 effective</sub> (min)</td><td align="center" valign="top" charoff="50">52</td><td align="center" valign="top" charoff="50">33</td><td align="center" valign="top" charoff="50">29</td><td align="center" valign="top" charoff="50">55</td><td align="center" valign="top" charoff="50">12</td><td align="center" valign="top" charoff="50">52</td><td align="center" valign="top" charoff="50">35</td><td align="center" valign="top" charoff="50">62</td></tr><tr><td align="left" valign="top" charoff="50">MRT<sub>0-<italic>t</italic></sub> (h)</td><td align="center" valign="top" charoff="50">1.24</td><td align="center" valign="top" charoff="50">0.79</td><td align="center" valign="top" charoff="50">0.69</td><td align="center" valign="top" charoff="50">1.33</td><td align="center" valign="top" charoff="50">0.28</td><td align="center" valign="top" charoff="50">1.25</td><td align="center" valign="top" charoff="50">0.84</td><td align="center" valign="top" charoff="50">1.50</td></tr><tr><td align="left" valign="top" charoff="50">CL (ml h<sup>−1</sup> kg<sup>−1</sup>)</td><td align="center" valign="top" charoff="50">4,607</td><td align="center" valign="top" charoff="50">3,870</td><td align="center" valign="top" charoff="50">4,590</td><td align="center" valign="top" charoff="50">4,953</td><td align="center" valign="top" charoff="50">2245</td><td align="center" valign="top" charoff="50">1,410</td><td align="center" valign="top" charoff="50">884</td><td align="center" valign="top" charoff="50">470</td></tr><tr><td align="left" valign="top" charoff="50"><italic>V</italic><sub>C</sub> (ml kg<sup>−1</sup>)</td><td align="center" valign="top" charoff="50">NC</td><td align="center" valign="top" charoff="50">NC</td><td align="center" valign="top" charoff="50">NC</td><td align="center" valign="top" charoff="50">NC</td><td align="center" valign="top" charoff="50">549</td><td align="center" valign="top" charoff="50">457</td><td align="center" valign="top" charoff="50">359</td><td align="center" valign="top" charoff="50">273</td></tr><tr><td align="left" valign="top" charoff="50"><italic>F</italic> (%)</td><td align="center" valign="top" charoff="50">62</td><td align="center" valign="top" charoff="50">58</td><td align="center" valign="top" charoff="50">49</td><td align="center" valign="top" charoff="50">45</td><td align="center" valign="top" charoff="50">100</td><td align="center" valign="top" charoff="50">100</td><td align="center" valign="top" charoff="50">100</td><td align="center" valign="top" charoff="50">100</td></tr></tbody></table><table-wrap-foot><fn id="t2-fn1"><p>AUC, area under the concentration-time curve; <italic>C</italic><sub>0</sub>, initial drug plasma concentration; <italic>C</italic><sub>max</sub>, observed maximum plasma concentration after administration; CL, total plasma clearance of drug after administration; <italic>F</italic>, relative bioavailability compared to i.v.; MRT, mean residence time of the unchanged drug in the systemic circulation; NC, not calculated; <italic>t</italic><sub>max</sub>, time of <italic>C</italic><sub>max</sub>; <italic>t</italic><sub>1/2</sub>, time required for the concentration to fall to 50% of its initial value; <italic>V</italic><sub>c</sub>, apparent volume of the central or plasma compartment.</p></fn><fn id="t2-fn2"><p>Data were examined using a non-compartment analysis.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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