Fluorenylalkanoic and benzoic acids as novel inhibitors of cell adhesion processes in leukocytes.
A series of fluoren-9-ylalkanoic and alkylbenzoic acids was prepared as simplified analogues of a previously reported series of antiinflammatory agents which act to inhibit neutrophil recruitment into inflamed tissue. The previous compounds ("leumedins") contained (alkoxycarbonyl)amino or benzoic acid moieties tethered to a fluorene ring. This functionality was replaced with simple structural elements. The new compounds were, in general, found to be more potent than the earlier series at inhibiting adherence of neutrophils to serum-coated wells or endothelial cells in vitro. Compound 9 was approximately 10-fold more potent than the previously reported FMOC-phenylalanine, of which it is an analogue. Similarly, compound 19 was superior in potency to its first generation progenitor, NPC 16570. The new compounds were shown to inhibit neutrophil adherence under conditions in which adherence is mediated by Mac-1 (CD11b/CD18) and LFA-1 (CD11a/CD18); they thus appear to target beta 2-integrins in their antiadhesion activity. These compounds provide a departure point for the further development of new cell adhesion inhibitors which should exhibit enhanced potency and a more selective mode of action.