Suppression of inflammation and structural damage in experimental arthritis through molecular targeted therapy with PPI-2458.
OBJECTIVE
To determine the disease-modifying activity and mechanism of action of the orally available methionine aminopeptidase type 2 inhibitor, [(1R)-1-carbamoyl-2-methyl-propyl]-carbamic acid-(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro [2.5] oct-6-yl ester (PPI-2458), in a rat model of peptidoglycan-polysaccharide (PG-PS)-induced arthritis.


METHODS
Arthritis was induced in rats by administration of PG-PS, causing tarsal joint swelling and histopathologic changes characteristic of rheumatoid arthritis (RA). PPI-2458, a potent irreversible methionine aminopeptidase type 2 inhibitor, was administered orally every other day at 1, 5, or 10 mg/kg.


RESULTS
In an in vitro osteoclastogenesis model, PPI-2458 potently inhibited osteoclast differentiation and bone resorption. In the rat PG-PS arthritis model, PPI-2458 afforded significant protection against established disease after therapeutic dosing. This in vivo activity of PPI-2458 was linked to the inhibition of methionine aminopeptidase type 2. Histopathologic assessment of affected joints showed improvement in processes of inflammation, bone resorption, and cartilage erosion, associated with significant improvement in all clinical indices. The protective effects of PPI-2458 against bone destruction in vivo, including the structural preservation of affected hind joints, correlated with improvements in bone histomorphometric markers, as determined by microfocal computed tomography and a significant decrease in systemic C-telopeptide of type I collagen, suggesting decreased osteoclast activity in vivo. Moreover, PPI-2458 prevented cartilage erosion as shown by a significant decrease in systemic cartilage oligomeric matrix protein.


CONCLUSIONS
The findings of this study suggest that PPI-2458 exerts disease-modifying activity in experimental arthritis through its direct inhibition of several pathophysiologic processes of this disease. These results provide a rationale for assessing the potential of PPI-2458 as a novel RA therapy.
Hannig
Gerhard
G
Praecis Pharmaceuticals, Waltham, Massachusetts 02451, USA. Gerhard.Hannig@praecis.com
Bernier
Sylvie G
SG
Hoyt
Jennifer G
JG
Doyle
Beth
B
Clark
Ed
E
Karp
Russell M
RM
Lorusso
Jeanine
J
Westlin
William F
WF
D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D001862:Bone Resorption / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004852:Epoxy Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006023:Glycoproteins / Q000037:antagonists & inhibitors; D006801:Humans; D007596:Joints / Q000473:pathology / Q000503:physiopathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010457:Peptidoglycan; D011134:Polysaccharides; D051381:Rats; D011917:Rats, Inbred Lew; D012720:Severity of Illness Index; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D006023:Glycoproteins; C488724:PPI 2458; D010457:Peptidoglycan; D011134:Polysaccharides; D000626:Aminopeptidases; C489895:Metap2 protein, rat; D014633:Valine