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dc.contributor.authorBaragana, Beatriz
dc.contributor.authorNorcross, Neil R
dc.contributor.authorWilson, Caroline
dc.contributor.authorPorzelle, Achim
dc.contributor.authorHallyburton, Irene
dc.contributor.authorGrimaldi, Raffaella
dc.contributor.authorOsuna-Cabello, Maria
dc.contributor.authorNorval, Suzanne
dc.contributor.authorRiley, Jennifer
dc.contributor.authorStojanovski, Laste
dc.contributor.authorSimeons, Frederick RC
dc.contributor.authorWyatt, Paul G
dc.contributor.authorDelves, Michael J
dc.contributor.authorMeister, Stephan
dc.contributor.authorDuffy, Sandra
dc.contributor.authorAvery, Vicky M
dc.contributor.authorWinzeler, Elizabeth A
dc.contributor.authorSinden, Robert E
dc.contributor.authorWittlin, Sergio
dc.contributor.authorFrearson, Julie A
dc.contributor.authorGray, David W
dc.contributor.authorFairlamb, Alan H
dc.contributor.authorWaterson, David
dc.contributor.authorCampbell, Simon F
dc.contributor.authorWillis, Paul
dc.contributor.authorRead, Kevin D
dc.contributor.authorGilbert, Ian H
dc.date.accessioned2018-01-23T01:01:08Z
dc.date.available2018-01-23T01:01:08Z
dc.date.issued2016
dc.identifier.issn0022-2623
dc.identifier.doi10.1021/acs.jmedchem.6b00723
dc.identifier.urihttp://hdl.handle.net/10072/143275
dc.description.abstractThe antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.relation.ispartofpagefrom9672
dc.relation.ispartofpageto9685
dc.relation.ispartofjournalJournal of Medicinal Chemistry
dc.relation.ispartofvolume59
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry not elsewhere classified
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry
dc.subject.fieldofresearchOrganic Chemistry
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.subject.fieldofresearchcode030499
dc.subject.fieldofresearchcode0304
dc.subject.fieldofresearchcode0305
dc.subject.fieldofresearchcode1115
dc.titleDiscovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorDuffy, Sandra
gro.griffith.authorAvery, Vicky M.


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