Effects of the cFMS Kinase Inhibitor 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) in Normal and Arthritic Rats

• Published in: The Journal of pharmacology and experimental therapeutics 2008-07, Vol.326 (1), p.41-50
• Main Authors: Conway, James G, Pink, Heather, Bergquist, Mandy L, Han, Bajin, Depee, Scott, Tadepalli, Sarva, Lin, Peiyuan, Crumrine, R Christian, Binz, Jane, Clark, Richard L, Selph, Jeffrey L, Stimpson, Stephen A, Hutchins, Jeff T, Chamberlain, Stanley D, Brodie, Thomas A
• Format: Article
• Language: English
• Subjects: Animals; Anisoles - pharmacology; Anisoles - therapeutic use; Arthritis, Experimental - drug therapy; Arthritis, Experimental - enzymology; Arthritis, Experimental - pathology; Cells, Cultured; Humans; Male; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rats; Rats, Inbred Lew; Receptor, Macrophage Colony-Stimulating Factor - antagonists & inhibitors; Sarcoma Viruses, Feline - drug effects; Sarcoma Viruses, Feline - enzymology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.107.129429

The cFMS (cellular homolog of the V-FMS oncogene product of the Susan McDonough strain of feline sarcoma virus) ( Proc Natl Acad Sci U S A 83: 3331–3335, 1986) kinase inhibitor 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) inhibits colony-stimulating factor (CSF)-1-induced monocyte growth and bone degradation in vitro and inhibits CSF-1 signaling through cFMS kinase in 4-day models in mice ( Proc Natl Acad Sci U S A 102: 16078, 2005). In the present study, the kinase selectivity of GW2580 was further characterized, and the effects of chronic treatment were evaluated in normal and arthritic rats. GW2580 selectively inhibited cFMS kinase compared with 186 other kinases in vitro and completely inhibited CSF-1-induced growth of rat monocytes, with an IC 50 value of 0.2 μM. GW2580 dosed orally at 25 and 75 mg/kg 1 and 5 h before the injection of lipopolysaccharide inhibited tumor necrosis factor-α production by 60 to 85%, indicating a duration of action of at least 5 h. In a 21-day adjuvant arthritis model, GW2580 dosed twice a day (b.i.d.) from days 0 to 21, 7 to 21, or 14 to 21 inhibited joint connective tissue and bone destruction as assessed by radiology, histology and bone mineral content measurements. In contrast, GW2580 did not affect ankle swelling in the adjuvant model nor did it affect ankle swelling in a model where local arthritis is reactivated by peptidoglycan polysaccharide polymers. GW2580 administered to normal rats for 21 days showed no effects on tissue histology and only modest changes in serum clinical chemistry and blood hematology. In conclusion, GW2580 was effective in preserving joint integrity in the adjuvant arthritis model while showing minimal effects in normal rats.