Abstract
Pannus formation, in both rheumatoid arthritis (RA) and collagen-induced arthritis (CIA), is angiogenesis-dependent. PPI-2458 [(1R)-1-carbamoyl-2-methyl]-carbamic acid-(3R,3S,5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)oxiranyl]-1-oxaspiro(2*5)oct-6-yl ester], a new fumagillin derivative known to inhibit methionine aminopeptidase 2 (MetAP-2) and endothelial proliferation at the late G1 phase, was evaluated in CIA rats to study its potential to involute synovitis. Arthritic syngeneic LOU rats received either a vehicle control or various dosages of oral, intravenous, or subcutaneous PPI-2458. Plasma samples were analyzed to determine a pharmacokinetic profile of PPI-2458, and whole blood was evaluated by flow cytometry to assess the effect on lymphocyte subsets. At 15 mg/kg i.v., 30 mg/kg s.c., or 100 mg/kg p.o., there was a significant reduction in clinical severity scores (p < 0.001) and blinded radiographic scores (p < 0.001) compared with vehicle control groups. Structural damage was virtually eliminated with PPI-2458. Continuous inhibition of MetAP-2 was needed to maintain benefits, although pannus involution could be achieved with the inhibitor when escape flares occurred. Pharmacokinetic analysis after a single p.o. dose showed a rapid Tmax value of 15 min followed by biphasic elimination (t½, ∼20 min and t½, ∼5 h) and an estimated oral bioavailability of ∼15%. Flow cytometry revealed a dose-dependent decrease in white blood cells and lymphocytes manifested as decreases in circulating CD3+ T cells and natural killer cells. PPI-2458, however, did not seem to be immunosuppressive, as determined by delayed-type hypersensitivity or IgG antibody assays. These studies indicate that the MetAP-2 inhibitor PPI-2458 can regress established CIA and that angiogenic mechanisms might be important targets in the treatment of other pannus-mediated diseases such as RA.
Footnotes
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This work was supported in part by the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [Grant AR42200]; VA Greater Los Angeles Healthcare System (to S.L.); and by Praecis Pharmaceuticals.
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doi:10.1124/jpet.108.148478.
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ABBREVIATIONS: RA, rheumatoid arthritis; MetAP-2, methionine aminopeptidase 2; CIA, collagen-induced arthritis; IFA, incomplete Freund's adjuvant; AUC, area under the curve; ELISA, enzyme-linked immunosorbent assay; DTH, delayed type hypersensitivity; WBC, white blood cells; NK, natural killer; q.o.d., every other day; q.d., every day.
- Received November 14, 2008.
- Accepted February 12, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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