Author: Mewshaw, Richard E. ; Hamilton, Gregory S. ; Danczak, Jennifer E. ; Feng, Ying ; Madden, Kip S. ; Perumattam, John ; Stanton, Lawrence W. ; Endemann, Gerda ; Bryant, Carmen M.

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.

01 Mar 1993·Agents and Actions

Prevention and suppression of experimental allergic encephalomyelitis by an orally active leukocyte recruitment inhibitor, NPC 16570

Article

Author: L. Noronha-Blob ; V. C. Lowe

An orally active leukocyte recruitment inhibitor, NPC 16570 (N-[9H-fluoren-9-ylethoxycarbonyl]-4-aminobenzoic acid), was evaluated in experimental allergic encephalomyelitis (EAE) in rats. The mean time of disease onset in control animals was 12 +/- 1 days, with peak average clinical scores of 2.5 +/- 0.2, accompanied by perivascular infiltration of inflammatory cells into the CNS. Daily administration (p.o.) of NPC 16570 reduced the clinical severity (by 70%) at 10 and 30 mg/kg, and at 100 mg/kg, no clinical symptoms were detected. When NPC 16570 (100 mg/kg) treatment was initiated 7 days after EAE induction, the severity (75% inhibition) and duration of the disease were attenuated; 2 out of 6 animals showed no overt clinical symptoms and perivascular cell infiltration was prevented, suggesting potential utility in autoimmune diseases.

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Indication	Highest Phase	Country/Location	Organization	Date
Hashimoto's Encephalitis	Discovery	US	Scios, Inc.	-
Hypersensitivity	Discovery	US	Scios, Inc.	-

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