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Potent cyclic peptide inhibitors of VLA-4 (?4?1 integrin)-mediated cell adhesion. Discovery of compounds like cyclo(MePhe-Leu-Asp-Val-d-Arg-d-Arg) (ZD7349) compatible with depot formulation

2000; Wiley; Volume: 6; Issue: 8 Linguagem: Inglês

10.1002/1099-1387(200008)6

1099-1387

Anand S. Dutta, James J. Gormley, Matthew Coath, Lorraine Hassall, Christopher F. Hayward, Paul Gellert, Rod S. Kittlety, Peter J. Alcock, Roger W. Ferguson, Tracy Halterman, Alec Jamieson, Jackie Moors, Julie M. Moores, Amanda Rees, Linda J. Wood, Christopher Reilly, Duncan Haworth,

Monoclonal and Polyclonal Antibodies Research

Journal of Peptide ScienceVolume 6, Issue 8 p. 398-412 Research Article Potent cyclic peptide inhibitors of VLA-4 (α4β1 integrin)-mediated cell adhesion. Discovery of compounds like cyclo(MePhe-Leu-Asp-Val-d-Arg-d-Arg) (ZD7349) compatible with depot formulation Anand S. Dutta, Corresponding Author Anand S. Dutta Anand.Dutta@AstraZeneca.com AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKDiscovery Research, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UKSearch for more papers by this authorJames J. Gormley, James J. Gormley AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorMatthew Coath, Matthew Coath AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorLorraine Hassall, Lorraine Hassall AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK AstraZeneca, 1800 Concord Pike, PO Box 15437, Wilmington, DE, USASearch for more papers by this authorChristopher F. Hayward, Christopher F. Hayward AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorPaul R. Gellert, Paul R. Gellert AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorRod S. Kittlety, Rod S. Kittlety AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorPeter J. Alcock, Peter J. Alcock AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorRoger Ferguson, Roger Ferguson AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorTracy Halterman, Tracy Halterman AstraZeneca, 1800 Concord Pike, PO Box 15437, Wilmington, DE, USASearch for more papers by this authorAlec Jamieson, Alec Jamieson AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorJackie A. Moors, Jackie A. Moors AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorJulie M. Moores, Julie M. Moores AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorAmanda Rees, Amanda Rees AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorLinda J. Wood, Linda J. Wood AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorChristopher F. Reilly, Christopher F. Reilly AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorDuncan Haworth, Duncan Haworth AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this author Anand S. Dutta, Corresponding Author Anand S. Dutta Anand.Dutta@AstraZeneca.com AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKDiscovery Research, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UKSearch for more papers by this authorJames J. Gormley, James J. Gormley AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorMatthew Coath, Matthew Coath AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorLorraine Hassall, Lorraine Hassall AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK AstraZeneca, 1800 Concord Pike, PO Box 15437, Wilmington, DE, USASearch for more papers by this authorChristopher F. Hayward, Christopher F. Hayward AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorPaul R. Gellert, Paul R. Gellert AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorRod S. Kittlety, Rod S. Kittlety AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorPeter J. Alcock, Peter J. Alcock AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorRoger Ferguson, Roger Ferguson AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorTracy Halterman, Tracy Halterman AstraZeneca, 1800 Concord Pike, PO Box 15437, Wilmington, DE, USASearch for more papers by this authorAlec Jamieson, Alec Jamieson AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorJackie A. Moors, Jackie A. Moors AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorJulie M. Moores, Julie M. Moores AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorAmanda Rees, Amanda Rees AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorLinda J. Wood, Linda J. Wood AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorChristopher F. Reilly, Christopher F. Reilly AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this authorDuncan Haworth, Duncan Haworth AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UKSearch for more papers by this author First published: 23 August 2000 https://doi.org/10.1002/1099-1387(200008)6:8 3.0.CO;2-1Citations: 16AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Additional structure–activity relationship studies on potent cyclic peptide inhibitors of very late antigen-4 (VLA-4) are reported. The new N- to C-terminal cyclic hexa-, hepta- and octapeptide inhibitors like cyclo(MeIle/MePhe-Leu-Asp-Val-X) (X=2–4 amino acids containing hydrophobic and/or basic side chains) were synthesized using solid phase peptide synthesis methods. The peptides were evaluated in in vitro cell adhesion assays and in in vivo inflammation models. Many of the peptides like cyclo(MePhe-Leu-Asp-Val-d-Arg-d-Arg) (ZD7349) (17), cyclo(MeIle-Leu-Asp-Val-d-Arg-d-Arg-d-Phe) (20), cyclo(MeIle-Leu-Asp-Val-d-Arg-d-Arg-MePhe) (21) and cyclo(MePhe-Leu-Asp-Val-d-Arg-d-Arg-d-Ala-d-Ala) (23) were potent inhibitors of VLA-4-mediated cell adhesion and inhibited ovalbumin-induced delayed type hypersensitivity (DTH) response in mice. The more potent compounds were highly selective and did not affect U937 cell adhesion to fibronectin (VLA-5), phorbolmyristate acetate or PMA-differentiated U937 cell adhesion to intercellular cell adhesion molecule-1 (ICAM-1)-expressing Chinese hamster ovary cells (LFA-1) and adenosine diphosphate (ADP)-induced platelet aggregation (GPIIb/IIIa). In contrast to the inhibitors like Ac-cyclo(d-Lys-d-Ile-Leu-Asp-Val) and cyclo(CH2CO-Ile-Leu-Asp-Val-Pip-CH2CO-Ile-Leu-Asp-Val-Pip) described earlier, the new compounds were much more compatible with the depot formulations based on poly(dl-lactide-co-glycolide) polymers. The hexapeptide cyclo(MePhe-Leu-Asp-Val-d-Arg-d-Arg) (ZD7349) (17) inhibited MOLT-4 cell adhesion to fibronectin and vascular cell adhesion molecule-1 (VCAM-1) with IC50 values of 260 and 330 nm, respectively, and did not show any significant effect against other integrins (IC50>300 μm). ZD7349 inhibited ovalbumin-induced DTH response in mice when administered continuously using a mini-pump (ED50 0.01 mg/kg/day) or when given as an s.c. or i.v. bolus injection at a dose of 1–10 mg/kg. ZD7349 was also active in type II collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) tests at a dose of 3–10 mg/kg. The peptide was released from some formulations over a period of 10–20 days. ZD7349 is currently undergoing pre-clinical investigation. Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd. Citing Literature Volume6, Issue8August 2000Pages 398-412 RelatedInformation