Effect of the inosine 5'-monophosphate dehydrogenase inhibitor BMS-566419 on rat cardiac allograft rejection.
Inosine 5'-monophosphate dehydrogenase (IMPDH) inhibition is a critical target in solid organ transplantation, and the development of mycophenolate mofetil (MMF) represents a major advance in transplant medicine. In this study, the in vitro and in vivo pharmacological effects of BMS-566419, a novel chemically synthesized IMPDH inhibitor, were compared to those of mycophenolic acid (MPA) and MMF based on results from several immunological experiments. The in vitro inhibitory activity of BMS-566419 on IMPDH type I/II, immune cell proliferation and antibody production from lipopolysaccharide (LPS)-stimulated B cells was similar, albeit slightly less potent than that of MPA. In a rat heterotopic cardiac transplant model, monotherapy using orally administered BMS-566419 60mg/kg or MMF 40mg/kg prolonged the median survival time (MST) of transplanted grafts in the vehicle group from 5 to 18 and 18.5 days, respectively. In the presence of a sub-therapeutic dose of FK506, BMS-566419 30mg/kg and MMF 20mg/kg showed identical efficacy with an MST of 21.5 days. In dinitrophenol-LPS-stimulated rats in which calcineurin inhibitors failed to inhibit antibody production, in vivo oral administration of BMS-566419 resulted in antibody production suppression with similar efficacy to MMF. The in vivo antibody production against alloantigen was also suppressed by MMF or BMS-566419 treatment. In addition, gastrointestinal toxicity, considered a dose-limiting factor of MMF, was reduced in BMS-566419 treatment. These results suggest that BMS-566419 and other chemically synthesized IMPDH inhibitors have beneficial pharmacological effects similar to those of MMF, and are potential pharmaceutical candidates in transplant indications.
Pharmacology Research Laboratories, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan. tomonori.nakanishi@jp.astellas.com
Tomonori
T
Nakanishi
Tatsuaki
T
Morokata
Kaori
K
Kubo
Hitomi
H
Umeno
Yoshiteru
Y
Eikyu
Yoshihiro
Y
Kozuki
Nobuo
N
Seki
D000166:Acridines / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D016027:Heart Transplantation; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007075:Immunoglobulin M / Q000378:metabolism; D007165:Immunosuppression Therapy; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D014184:Transplantation, Homologous
D000166:Acridines; D007075:Immunoglobulin M; C523435:N-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2-fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide; D010879:Piperazines; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid