N-acyl-L-phenylalanine derivatives as potent VLA-4 antagonists that mimic a cyclic peptide conformation.
A series of N-benzylpyroglutamyl-L-phenylalanine derivatives bearing carbamoyl substituents in the 3- or 4-positions was prepared and assayed for inhibition of the interaction between VCAM and VLA-4. Potent inhibition was observed in a number of analogues with substitution in the 4-position favored over the 3-position. A crystal structure of the key intermediate 25 indicates that it accesses a low energy conformation which closely matches key pharmacophores of a structurally characterized cyclic peptide.
Chen
Li
L
Roche Research Center, Hoffmann-La Roche Inc, Nutley, NJ 07110, USA. li.chen@roche.com
Tilley
Jefferson
J
Trilles
Richard V
RV
Yun
Weiya
W
Fry
David
D
Cook
Charles
C
Rowan
Karen
K
Schwinge
Virginia
V
Campbell
Robert
R
D002460:Cell Line; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D018716:Molecular Mimicry; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D039041:Integrin alpha4beta1; D016023:Integrins; D010456:Peptides, Cyclic; D016201:Receptors, Lymphocyte Homing; D010649:Phenylalanine