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.
Nakanishi
Tomonori
T
Pharmacology Research Laboratories, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan. tomonori.nakanishi@jp.astellas.com
Morokata
Tatsuaki
T
Kubo
Kaori
K
Umeno
Hitomi
H
Eikyu
Yoshiteru
Y
Kozuki
Yoshihiro
Y
Seki
Nobuo
N
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