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Immunosuppressive properties of a series of novel inhibitors of the monocarboxylate transporter MCT-1.

Paul, Clara LU ; Qi, Zhongquan LU ; Murray, Clare M; Ferguson, Douglas; Bundick, Robert V; Donald, David K and Ekberg, Henrik LU (2012) In Transplant international : official journal of the European Society for Organ Transplantation
Abstract
We have recently described the immunosuppressive properties of AR-C117977 and AR-C122982, representatives of a group of compounds identified as inhibitors of lactate transporters (monocarboxylate transporters; MCTs). These compounds demonstrate the potential therapeutic usefulness of inhibiting MCT-1, but their physical and metabolic properties made them unsuitable for further development. We have therefore tried to find analogues with similar immunosuppressive efficacy and a more suitable profile for oral administration. Five analogues of AR-C117977 were synthesised and screened for binding to the transporter, for inhibition of proliferation of both human and rat lymphocytes, for in vivo activity in a model of graft-versus-host (GvH)... (More)
We have recently described the immunosuppressive properties of AR-C117977 and AR-C122982, representatives of a group of compounds identified as inhibitors of lactate transporters (monocarboxylate transporters; MCTs). These compounds demonstrate the potential therapeutic usefulness of inhibiting MCT-1, but their physical and metabolic properties made them unsuitable for further development. We have therefore tried to find analogues with similar immunosuppressive efficacy and a more suitable profile for oral administration. Five analogues of AR-C117977 were synthesised and screened for binding to the transporter, for inhibition of proliferation of both human and rat lymphocytes, for in vivo activity in a model of graft-versus-host (GvH) response in the rat, and in high- and low-responder cardiac transplant models in the rat. There was a good correlation between levels of binding of the five analogues to MCT and their inhibition of lymphocyte proliferation in human and rat cells. Furthermore, activity in both the GvH response and the cardiac transplant models correlated well with the determined concentrations of test compound in plasma. These findings on new analogues of MCT-1 inhibitors have taken us further towards defining the pharmacokinetic properties that may help to identify future drug candidates among inhibitors of MCT-1. (Less)
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published
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Transplant international : official journal of the European Society for Organ Transplantation
publisher
Springer
external identifiers
  • WOS:000312538600006
  • PMID:23137339
  • Scopus:84871331030
ISSN
1432-2277
DOI
10.1111/j.1432-2277.2012.01579.x
language
English
LU publication?
yes
id
0598e42f-1b51-43c9-a432-315c032b5799 (old id 3219141)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23137339?dopt=Abstract
date added to LUP
2012-12-03 14:00:31
date last changed
2016-11-13 04:28:21
@misc{0598e42f-1b51-43c9-a432-315c032b5799,
  abstract     = {We have recently described the immunosuppressive properties of AR-C117977 and AR-C122982, representatives of a group of compounds identified as inhibitors of lactate transporters (monocarboxylate transporters; MCTs). These compounds demonstrate the potential therapeutic usefulness of inhibiting MCT-1, but their physical and metabolic properties made them unsuitable for further development. We have therefore tried to find analogues with similar immunosuppressive efficacy and a more suitable profile for oral administration. Five analogues of AR-C117977 were synthesised and screened for binding to the transporter, for inhibition of proliferation of both human and rat lymphocytes, for in vivo activity in a model of graft-versus-host (GvH) response in the rat, and in high- and low-responder cardiac transplant models in the rat. There was a good correlation between levels of binding of the five analogues to MCT and their inhibition of lymphocyte proliferation in human and rat cells. Furthermore, activity in both the GvH response and the cardiac transplant models correlated well with the determined concentrations of test compound in plasma. These findings on new analogues of MCT-1 inhibitors have taken us further towards defining the pharmacokinetic properties that may help to identify future drug candidates among inhibitors of MCT-1.},
  author       = {Paul, Clara and Qi, Zhongquan and Murray, Clare M and Ferguson, Douglas and Bundick, Robert V and Donald, David K and Ekberg, Henrik},
  issn         = {1432-2277},
  language     = {eng},
  month        = {11},
  publisher    = {ARRAY(0x8cad508)},
  series       = {Transplant international : official journal of the European Society for Organ Transplantation},
  title        = {Immunosuppressive properties of a series of novel inhibitors of the monocarboxylate transporter MCT-1.},
  url          = {http://dx.doi.org/10.1111/j.1432-2277.2012.01579.x},
  year         = {2012},
}