Discovery of PG545

• Verfasst von: Ferro, Vito [VerfasserIn]
• Verfasst von: Harenberg, Job [VerfasserIn]
• Titel: Discovery of PG545
• Titelzusatz: a highly potent and simultaneous inhibitor of angiogenesis, tumor growth, and metastasis
• Verf.angabe: Vito Ferro, Ligong Liu, Ken D. Johnstone, Norbert Wimmer, Tomislav Karoli, Paul Handley, Jessica Rowley, Keith Dredge, Cai Ping Li, Edward Hammond, Kat Davis, Laura Sarimaa, Job Harenberg, and Ian Bytheway
• E-Jahr: 2012
• Jahr: March 29, 2012
• Umfang: 14 S.
• Fussnoten: Gesehen am 21.09.2018
• Titel Quelle: Enthalten in: Journal of medicinal chemistry
• Ort Quelle: Washington, DC : ACS, 1959
• Jahr Quelle: 2012
• Band/Heft Quelle: 55(2012), 8, Seite 3804-3813
• ISSN Quelle: 1520-4804
• DOI: doi:10.1021/jm201708h
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 158120535X

Abstract

Increasing 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 3β-cholestanyl 2,3,4,6-tetra-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β-d-glucopyranoside, tridecasodium salt (PG545, 18) as a clinical candidate. Compound 18 was recently evaluated in a phase I clinical trial in cancer patients.