title: In vitro and in vivo characterization of AS2643361, a novel and highly potent inosine 5'-monophosphate dehydrogenase inhibitor.
abstract: Inosine 5'-monophosphate (IMP) dehydrogenase is a critical target in solid organ transplantation. To this end, the development of mycophenolate mofetil (MMF) represents a major advance in transplant medicine. Here, we investigated the in vitro and in vivo pharmacological effects of a novel IMP dehydrogenase inhibitor, AS2643361, in several immunological and non-immunological models. The in vitro inhibitory activity of AS2643361 on immune cell and endothelial cell proliferation and on antibody production from lipopolysaccharide-stimulated B cells, was significantly more potent than that of mycophenolic acid, the active form of MMF, despite the similar potency of these compounds on IMP dehydrogenase. In a rat heterotopic cardiac transplant model, monotherapy using orally administered AS2643361 at 10 or 20mg/kg/day prolonged the median graft survival time from 6 to 16 and 19days, respectively. In dinitrophenol-lipopolysaccharide stimulated rats, oral administration of AS2643361 at 2.5, 5 or 10mg/kg/day resulted in suppression of antibody production. In vivo antibody production against alloantigen was also suppressed by AS2643361 treatment at 5 or 10mg/kg/day. Furthermore, treatment with AS2543361 effectively inhibited balloon injury induced-intimal thickening, which is a major cause of late allograft loss. Overall, the in vivo activity of AS2643361 was over two-fold more potent than that of MMF. In addition, gastrointestinal toxicity, considered a dose-limiting factor for MMF, was reduced with AS2643361 treatment. These results suggest AS2643361 has higher potency and less toxicity than MMF, making it a potential candidate for treatment of acute and chronic rejection in transplant medicine.
authors.affiliation: Astellas Research Institute of America LLC, Transplantation Immunology, Skokie, IL 60077, USA. tomonori.nakanishi@us.astellas.com
authors.forename: Tomonori
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kozuki
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Eikyu
authors.forename: Kaori
authors.initials: K
authors.lastname: Kubo
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kawato
authors.forename: Takanori
authors.initials: T
authors.lastname: Marui
authors.forename: Nobuo
authors.initials: N
authors.lastname: Seki
authors.forename: Taro
authors.initials: T
authors.lastname: Masunaga
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Morokata
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D041981:Gastrointestinal Tract / Q000187:drug effects; D006084:Graft Rejection / Q000188:drug therapy; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D051381:Rats; D013830:Thiadiazoles / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D057772:Vascular System Injuries / Q000188:drug therapy / Q000209:etiology
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; C570851:N-((4-fluorophenyl)(1-methyl-1H-imidazol-2-yl)methyl)-2-methyl-3-(1,2,4-thiadiazol-5-yl)-1H-indole-6-carboxamide; D013830:Thiadiazoles; D007168:IMP Dehydrogenase