Effects of the cFMS kinase inhibitor 5-(3-methoxy-4-((4-methoxybenzyl) oxy)benzyl)pyrimidine-2,4-diamine (GW2580) in normal and arthritic rats
Effects of the cFMS kinase inhibitor 5-(3-methoxy-4-((4-methoxybenzyl) oxy)benzyl)pyrimidine-2,4-diamine (GW2580) in normal and arthritic rats
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DOI：
10.1124/jpet.107.129429
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发表时间：
2008-07-01
影响因子：
3.5
通讯作者：
Brodie, Thomas A.
中科院分区：
文献类型：
--
作者：
Conway, James G.;Pink, Heather;Brodie, Thomas A.
cFMS（猫肉瘤病毒苏珊麦克多诺株的V-FMS癌基因产物的细胞同源物）（Proc Natl Acad Sci U S A 83：3331-3335，1986）激酶抑制剂5-（3-甲氧基-4-（（4-甲氧基苄基）氧基）苄基）嘧啶-2，4-二胺（GW 2580）在体外抑制集落刺激因子（CSF）-1诱导的单核细胞生长和骨降解，并在4-小鼠中的日模型（Proc Natl Acad Sci U S A 102：16078，2005）。在本研究中，进一步表征了GW 2580的激酶选择性，并在正常和关节炎大鼠中评估了慢性治疗的效果。与186种其他激酶相比，GW 2580在体外选择性抑制cFMS激酶，并完全抑制CSF-1诱导的大鼠单核细胞生长，IC（50）值为0.2 μ M。在注射脂多糖前1和5 h经口给予25和75 mg/kg GW 2580可抑制肿瘤坏死因子-α产生60 - 85%，表明作用持续时间至少为5 h。在21天佐剂性关节炎模型中，GW 2580每天给药两次（b.i.d.）从第0天到第21天、第7天到第21天、或第14天到第21天，通过放射学、组织学和骨矿物质含量测量评估，抑制了关节结缔组织和骨破坏。相反，GW 2580不影响佐剂模型中的踝关节肿胀，也不影响局部关节炎被肽聚糖多糖聚合物再激活的模型中的踝关节肿胀。对正常大鼠给药21天的GW 2580对组织组织学没有影响，血清临床化学和血液学仅发生适度变化。总之，GW 2580在佐剂性关节炎模型中有效地保持关节完整性，而在正常大鼠中显示出最小的作用。
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 mu M. GW2580 dosed orally at 25 and 75 mg/kg 1 and 5 h before the injection of lipopolysaccharide inhibited tumor necrosis factor-alpha 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.