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dc.contributor.authorFerro, V
dc.contributor.authorLiu, L
dc.contributor.authorJohnstone, KD
dc.contributor.authorWimmer, N
dc.contributor.authorKaroli, T
dc.contributor.authorHandley, P
dc.contributor.authorRowley, J
dc.contributor.authorDredge, K
dc.contributor.authorLi, CP
dc.contributor.authorHammond, E
dc.contributor.authorDavis, K
dc.contributor.authorSarimaa, L
dc.contributor.authorHarenberg, J
dc.contributor.authorBytheway, I
dc.date.accessioned2017-05-03T15:37:53Z
dc.date.available2017-05-03T15:37:53Z
dc.date.issued2012
dc.date.modified2013-06-17T23:34:10Z
dc.identifier.issn0022-2623
dc.identifier.doi10.1021/jm201708h
dc.identifier.urihttp://hdl.handle.net/10072/48699
dc.description.abstractIncreasing the aglycone lipophilicity of a series of polysulfated oligosaccharide glycoside heparan sulfate (HS) mimetics via attachment of a steroid or long chain alkyl group resulted in compounds with significantly improved in vitro and ex vivo antiangiogenic activity. The compounds potently inhibited heparanase and HS-binding angiogenic growth factors and displayed improved antitumor and antimetastatic activity in vivo compared with the earlier series. Preliminary pharmacokinetic analyses also revealed significant increases in half-life following iv dosing, ultimately supporting less frequent dosing regimens in preclinical tumor models compared with other HS mimetics. The compounds also displayed only mild anticoagulant activity, a common side effect usually associated with HS mimetics. These efforts led to the identification of 3߭cholestanyl 2,3,4,6-tetra-O-sulfo-a-d-glucopyranosyl-(1?4)-2,3,6-tri-O-sulfo-a-d-glucopyranosyl-(1?4)-2,3,6-tri-O-sulfo-a-d-glucopyranosyl-(1?4)-2,3,6-tri-O-sulfo-߭d-glucopyranoside, tridecasodium salt (PG545, 18) as a clinical candidate. Compound 18 was recently evaluated in a phase I clinical trial in cancer patients.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.publisher.placeUnited States
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom3804
dc.relation.ispartofpageto3813
dc.relation.ispartofissue8
dc.relation.ispartofjournalJournal of Medicinal Chemistry
dc.relation.ispartofvolume55
dc.rights.retentionY
dc.subject.fieldofresearchClinical Pharmacology and Therapeutics
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry
dc.subject.fieldofresearchOrganic Chemistry
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.subject.fieldofresearchcode111502
dc.subject.fieldofresearchcode0304
dc.subject.fieldofresearchcode0305
dc.subject.fieldofresearchcode1115
dc.titleDiscovery of PG545: A Highly Potent and Simultaneous Inhibitor of Angiogenesis, Tumor Growth, and Metastasis
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.rights.copyrightSelf-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the authors for more information.
gro.date.issued2012
gro.hasfulltextNo Full Text
gro.griffith.authorSarimaa, Laura J.
gro.griffith.authorRowley, Jessica


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