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TRAM‐34, a potential new drug for transplant rejection and stroke
Author(s) -
Wulff Heike,
Chen YiJe,
Tran Lien,
Homerick Daniel,
O'Donnell Martha,
Gregory Clare
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a538-d
Subject(s) - medicine , restenosis , stroke (engine) , angiogenesis , pharmacology , rosiglitazone , immunosuppression , transplantation , insulin , stent , mechanical engineering , engineering
The calcium‐activated potassium channel KCa3.1 plays an important role in the proliferation and migration of T cells, macrophages, vascular smooth muscle and endothelial cells. KCa3.1 has therefore been proposed as a new drug target for the treatment of restenosis, atherosclerosis, tumor angiogenesis and transplant rejection. Using clotrimazole as a template, we designed a selective small molecule KCa3.1 blocker called TRAM‐34 (EC 50 = 20 nM) and showed that it suppressed T cell proliferation and synergized with cyclosporine. TRAM‐34 has a half‐life of 1.8 h in rats and of 2.1 h in rhesus macaques and exhibits no signs of acute of long‐term toxicity in rats. We previously demonstrated that TRAM‐34 effectively prevents restenosis in a rat model of balloon catheter and atherosclerosis development in apolipoprotein E knockout mice. Encouraged by these results we are now testing TRAM‐34 in models of acute transplant rejection and ischemic stroke. In middle cerebral artery occlusion (90 min) with 7‐day reperfusion in male Wistar rats TRAM‐34 at 10 mg/kg reduces infarct area, infiltration of ED1 + microglia/macrophages and brain shrinkage by ~50%. In a heterotopic heart transplant model (Brown Norway to Lewis) TRAM‐34 prolongs graft survival. Combinations with low doses of cyclosporine are currently being tested. Supported by AHA, NIH and UC Davis