The hold has been lifted. Now we have the first published work relating to this compound's suitability for RA:
>>Published online before print July 12, 2004
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0404105101
Medical Sciences
A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis
Sylvie G. Bernier *, Douglas D. Lazarus *, Edward Clark *, Beth Doyle *, Matthew T. Labenski , Charles D. Thompson , William F. Westlin *, and Gerhard Hannig *
Departments of *Preclinical Research and Analytical Pharmacology, Praecis Pharmaceuticals, Incorporated, 830 Winter Street, Waltham, MA 02451
Communicated by R. L. Erikson, Harvard University, Cambridge, MA, June 9, 2004 (received for review November 15, 2003)
The hallmark of rheumatoid arthritis (RA) is the progressive destruction of articular joints, characterized by invasive synovial hyperplasia and pathological neovascularization. Here we report that PPI-2458, a member of the fumagillin class of irreversible methionine aminopeptidase-2 (MetAP-2) inhibitors, potently inhibits the proliferation of human fibroblast-like synoviocytes (HFLS-RA), derived from RA patients, with a growth inhibitory concentration 50 (GI50) of 0.04 nM and a maximum inhibition of >95% at 1 nM. Human umbilical vein endothelial cells (HUVEC) are similarly inhibited in proliferation by PPI-2458 (GI50, 0.2 nM). We developed a method to measure the level of MetAP-2 enzyme inhibition after exposure to PPI-2458 and demonstrate that growth inhibition of PPI-2458-sensitive HFLS-RA and HUVEC is linked to MetAP-2 enzyme inhibition, in a dose-dependent fashion. The secretion of several inflammatory mediators such as IL-6 and vascular endothelial growth factor from activated HFLS-RA was not inhibited by PPI-2458. The CNS toxicity profile of PPI-2458, determined by the incidence of seizures, is significantly improved over that of the parental compound TNP-470. In the rat model of peptidoglycan-polysaccharide-induced arthritis, PPI-2458 significantly attenuated paw swelling when therapeutically administered after the onset of chronic disease. We suggest that the mechanism of PPI-2458 action, highly selective and potent antiproliferative activity on HFLS-RA and HUVEC in vitro, a significantly improved CNS toxicity profile, and marked attenuation of chronic disease in the rat peptidoglycan-polysaccharide arthritis model in vivo, positions this compound as a drug for the treatment of RA.<<
PRCS has made a little noise about PPI-2458 for this indication, so finding this before the company issued a PR (IF they issue a PR) may not be a huge trading opportunity.
Cheers, Tuck |
