The Discovery of VLA-4 Antagonists

Author(s): Jefferson W. Tilley, Li Chen, Achyutharao Sidduri, Nader Fotouhi

Journal Name: Current Topics in Medicinal Chemistry

Volume 4 , Issue 14 , 2004

Become EABM
Become Reviewer


Starting with a cyclic peptide of moderate potency as a VLA-4 antagonist, highly potent and conformationally defined cyclic peptides were developed incorporating a constrained tyrosine and an achiral Asp-Pro spacer. N-Acyl phenylalanine derivatives were also discovered to have VLA-4 antagonist activity. During the course of development of this series, we found that the active acylphenylalanines mimic the pharmacophores present in the cyclic peptides and hypothesized that they bind to the same site on VLA-4. This insight guided our optimization strategy. Based on the emerging SAR, as well as insights from the recent X-ray crystal structure of the integrin αvβ3 bound to a RGD containing cyclic peptide, we propose a binding model for these compounds.

Keywords: vla-4 antagonists, vascular cell adhesion molecule, asthma, inflammatory bowel disease, vcam/vla-4 interaction, acylphenylalanines, sar

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2004
Page: [1509 - 1523]
Pages: 15
DOI: 10.2174/1568026043387502
Price: $65

Article Metrics

PDF: 4