FLUORENYLALKANOIC AND BENZOIC-ACIDS AS NOVEL INHIBITORS OF CELL-ADHESION PROCESSES IN LEUKOCYTES

A series of fluoren-9-ylalkanoic and alkylbenzoic acids was prepared a s simplified analogues of a previously reported series of antiinflamma tory agents which act to inhibit neutrophil recruitment into inflamed tissue. The previous compounds (''leumedins'') contained (alkoxycarbon yl)amino or benzoic acid moieties tethered to a fluorene ring. This fu nctionality was replaced with simple structural elements. The new comp ounds were, in general, found to be more potent than the earlier serie s at inhibiting adherence of neutrophils to serum-coated wells or endo thelial cells in vitro. Compound 9 was approximately 10-fold more pote nt 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 inhi bit neutrophil adherence under conditions in which adherence is mediat ed by Mac-1 (CD11b/CD18) and LFA-1 (CD11a/CD18); they thus appear to t arget beta(2)-integrins in their antiadhesion activity. These compound s provide a departure point for the further development of new cell ad hesion inhibitors which should exhibit enhanced potency and a more sel ective mode of action.