The discovery of VLA-4 antagonists.
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 alphavbeta3 bound to a RGD containing cyclic peptide, we propose a binding model for these compounds.
Tilley
Jefferson W
JW
Roche Research Center, 340 Kingsland St., Nutely, NJ 07110, USA. Jefferson.Tilley@roche.com
Chen
Li
L
Sidduri
Achyutharao
A
Fotouhi
Nader
N
D006801:Humans; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D018716:Molecular Mimicry; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D039041:Integrin alpha4beta1; D010456:Peptides, Cyclic