PMID- 20832515
OWN - NLM
STAT- MEDLINE
DCOM- 20110303
LR  - 20161125
IS  - 1878-1705 (Electronic)
IS  - 1567-5769 (Linking)
VI  - 10
IP  - 11
DP  - 2010 Nov
TI  - Effect of the inosine 5'-monophosphate dehydrogenase inhibitor BMS-566419 on 
      renal fibrosis in unilateral ureteral obstruction in rats.
PG  - 1434-9
LID - 10.1016/j.intimp.2010.08.011 [doi]
AB  - Chronic allograft nephropathy (CAN) is a major cause of late allograft loss. One 
      morphological characteristic of CAN is renal interstitial fibrosis. Mycophenolate 
      mofetil (MMF), the inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitor, has 
      been reported to attenuate the progression of renal interstitial fibrosis. 
      However, the question of whether the newly synthesized IMPDH inhibitors with 
      structures different from MMF have an antifibrotic effect remains unanswered. We 
      evaluated the antifibrotic effects of BMS-566419, a chemically synthesized IMPDH 
      inhibitor, using an experimental rat model, unilateral ureteral obstruction 
      (UUO), in comparison with those of MMF. Expression levels of monocyte 
      chemoattractant protein-1 (MCP-1) and transforming growth factor-beta1 (TGF-beta1), 
      which play important roles in UUO-induced renal fibrosis, were also investigated 
      to determine the mechanism by which BMS-566419 affects the progression of renal 
      fibrosis. After 14 days of UUO, interstitial fibrosis was frequently observed in 
      the renal cortex of rats administered vehicle control. BMS-566419 by oral 
      administration showed a significant and dose-dependent suppressive effect on 
      UUO-induced renal fibrosis in histopathological experiments. BMS-566419 treatment 
      also decreased collagen content, as indicated by hydroxyproline concentration, 
      and the expression of collagen type 1 mRNA. BMS-566419 also decreased the 
      expression of mRNA for both MCP-1 and TGF-beta1. The antifibrotic effects of 
      treatment with BMS-566419 at 60 mg/kg seemed comparable to those with MMF at 40 
      mg/kg. 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 the treatment of fibrotic renal 
      disease, including CAN.
CI  - Copyright (c) 2010 Elsevier B.V. All rights reserved.
FAU - Nakanishi, Tomonori
AU  - Nakanishi T
AD  - Pharmacology Research Laboratories, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, 
      Japan. tomonori.nakanishi@jp.astellas.com
FAU - Morokata, Tatsuaki
AU  - Morokata T
FAU - Noto, Takahisa
AU  - Noto T
FAU - Kubo, Kaori
AU  - Kubo K
FAU - Umeno, Hitomi
AU  - Umeno H
FAU - Kinugasa, Fumitaka
AU  - Kinugasa F
FAU - Eikyu, Yoshiteru
AU  - Eikyu Y
FAU - Kozuki, Yoshihiro
AU  - Kozuki Y
FAU - Seki, Nobuo
AU  - Seki N
LA  - eng
PT  - Journal Article
DEP - 20100909
PL  - Netherlands
TA  - Int Immunopharmacol
JT  - International immunopharmacology
JID - 100965259
RN  - 0 (Acridines)
RN  - 0 (Chemokine CCL2)
RN  - 0 
      (N-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2-fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide)
RN  - 0 (Piperazines)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 9007-34-5 (Collagen)
RN  - EC 1.1.1.205 (IMP Dehydrogenase)
RN  - HU9DX48N0T (Mycophenolic Acid)
RN  - RMB44WO89X (Hydroxyproline)
SB  - IM
MH  - Acridines/*therapeutic use
MH  - Animals
MH  - Chemokine CCL2/analysis
MH  - Chronic Disease
MH  - Collagen/analysis
MH  - Fibrosis
MH  - Hydroxyproline/analysis
MH  - IMP Dehydrogenase/*antagonists & inhibitors
MH  - Kidney Cortex/drug effects/pathology
MH  - Kidney Diseases/*drug therapy/etiology/*pathology
MH  - Male
MH  - Mycophenolic Acid/analogs & derivatives/therapeutic use
MH  - Piperazines/*therapeutic use
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Transforming Growth Factor beta1/analysis
MH  - Ureteral Obstruction/*complications
EDAT- 2010/09/14 06:00
MHDA- 2011/03/04 06:00
CRDT- 2010/09/14 06:00
PHST- 2010/01/22 00:00 [received]
PHST- 2010/08/12 00:00 [revised]
PHST- 2010/08/18 00:00 [accepted]
PHST- 2010/09/14 06:00 [entrez]
PHST- 2010/09/14 06:00 [pubmed]
PHST- 2011/03/04 06:00 [medline]
AID - S1567-5769(10)00265-1 [pii]
AID - 10.1016/j.intimp.2010.08.011 [doi]
PST - ppublish
SO  - Int Immunopharmacol. 2010 Nov;10(11):1434-9. doi: 10.1016/j.intimp.2010.08.011. 
      Epub 2010 Sep 9.