Diamine containing VLA-4 antagonists.
Design and synthesis of a library as potential VLA-4 antagonists has been accomplished, based around a proposed pharmacophoric model. Compounds possessing submicromolar potency were identified and structure-activity relationships were seen across the library. Further derivatisation produced compounds with IC(50)'s <10 nmol for inhibiting the VLA-4 mediated binding of fibronectin to RAMOS cells, providing an ideal starting point for a lead optimisation Programme.
Astles
P C
PC
Aventis Pharma Ltd, Dagenham Research Centre, Dagenham, RM10 7XS, Essex, UK.
Harris
N V
NV
Morley
A D
AD
D002448:Cell Adhesion / Q000187:drug effects; D003959:Diamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D003959:Diamines; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing