Imide and lactam derivatives of N-benzylpyroglutamyl-L-phenylalanine as VCAM/VLA-4 antagonists.
A series of imides and lactams derived from 4-amino-N-benzylpyroglutamyl-L-phenylalanine was prepared and evaluated for activity as VCAM/VLA-4 antagonists. Imides were more potent than the corresponding lactams; several had subnanomolar IC50s in an ELISA based assay and were also highly effective at blocking VLA-4 expressing Ramos cell binding to VCAM coated plates.
Tilley
J W
JW
Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. jefferson.tilley@roche.com
Kaplan
G
G
Rowan
K
K
Schwinge
V
V
Wolitzky
B
B
D002448:Cell Adhesion / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007094:Imides / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors*; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives*; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D004151:Dipeptides; D007094:Imides; D039041:Integrin alpha4beta1; D016023:Integrins; D007769:Lactams; D016201:Receptors, Lymphocyte Homing; D010649:Phenylalanine; D011761:Pyrrolidonecarboxylic Acid