Immunosuppressive properties of a series of novel inhibitors of the monocarboxylate transporter MCT-1.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3219141
- author
- Paul, Clara LU ; Qi, Zhongquan LU ; Murray, Clare M ; Ferguson, Douglas ; Bundick, Robert V ; Donald, David K and Ekberg, Henrik LU
- organization
- publishing date
- 2012-11-08
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Transplant international : official journal of the European Society for Organ Transplantation
- publisher
- Springer
- external identifiers
-
- wos:000312538600006
- pmid:23137339
- scopus:84871331030
- pmid:23137339
- ISSN
- 1432-2277
- DOI
- 10.1111/j.1432-2277.2012.01579.x
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Emergency medicine/Medicine/Surgery (013240200), Renal Research Unit (013242210)
- 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
- 2016-04-04 09:24:27
- date last changed
- 2022-04-15 23:10:30
@article{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 = {{Springer}},
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}},
doi = {{10.1111/j.1432-2277.2012.01579.x}},
year = {{2012}},
}