The novel IMPDH inhibitor VX-497 prolongs skin graft survival and improves graft versus host disease in mice.
VX-497 is the first inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor generated in a structure-based drug design program specifically addressing the tolerability problems of currently available immunosuppressive drugs. The pharmacological activity of the compound has been examined in murine skin transplantation and graft versus host disease (GVHD) models. In the skin transplant study, trunk skin grafts from Balb/c mice were grafted onto C57Bl/6 mice. Mice were administered vehicle or VX-497 twice daily until day 10. Mean survival of skin grafts on vehicle-treated animals was 9.9 +/- 0.9 days. Graft survival was prolonged significantly in animals treated with VX-497 to 13.2 +/- 1.2 (p < 0.001, Kaplan Meier Log-Rank test) days in the 50 mg/kg group and 13.9 +/- 1.0 (p < 0.001) days in the 85 mg/kg group. In the GVHD study, 150 x 10(6) nonadherent splenocytes from B6 mice were injected intravenously into the F1 hybrid strain B6DBA/2. Groups of animals (n = 6) were administered vehicle or 50 or 100 mg/kg VX-497 b.i.d for 8 days. Animals were sacrificed and spleen weights and interferon-gamma (IFN-gamma) serum levels were determined by enzyme-linked immunosorbent assay. In addition, spontaneous spleen cell proliferation was measured using a 3H-thymidine uptake assay. Isografted F1 animals served as controls. GVHD developed in the vehicle-treated allografted F1 mice and treatment with VX-497 improved all manifestations of the disease significantly. The 2.9-fold increase in spleen weight in allografted animals was reduced to a 1.6-fold increase in the VX-497-treated mice. Serum IFN-gamma levels were increased 54-fold in the vehicle group while there was a 7.4-fold increase in VX-497-treated animals. Spontaneous spleen cell proliferation was increased 9.9-fold in the absence of VX-497 and there was a 3.5-fold increase in its presence. Thus, VX-497 has been shown to be effective in both a skin transplantation and a GVHD model in the mouse. The demonstrated pharmacological activity of VX-497 in these murine transplantation models warrants further evaluation of the drug in transplantation indications.
Decker
C J
CJ
Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139-4242, USA.
Heiser
A D
AD
Chaturvedi
P R
PR
Faust
T J
TJ
Ku
G
G
Moseley
S
S
Nimmesgern
E
E
D000818:Animals; D002219:Carbamates / Q000737:chemistry / Q000627:therapeutic use*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D006084:Graft Rejection / Q000503:physiopathology; D006085:Graft Survival / Q000187:drug effects*; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007371:Interferon-gamma / Q000097:blood; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D010671:Phenylurea Compounds / Q000737:chemistry / Q000627:therapeutic use*; D012867:Skin / Q000276:immunology / Q000473:pathology; D016038:Skin Transplantation / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology
D002219:Carbamates; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; C407002:N-3-(3-(3-methoxy-4-oxazol-5-ylphenyl)ureido)benzylcarbamic acid tetrahydrofuran-3-yl ester; D010671:Phenylurea Compounds; D007371:Interferon-gamma; D007168:IMP Dehydrogenase