title: Immunosuppressive properties of a series of novel inhibitors of the monocarboxylate transporter MCT-1.
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.
authors.affiliation: Department of Nephrology and Transplantation, Skane University Hospital, Malmo, Sweden. clara.pahlman@med.lu.se
authors.forename: Clara
authors.initials: C
authors.lastname: Påhlman
authors.forename: Zhongquan
authors.initials: Z
authors.lastname: Qi
authors.forename: Clare M
authors.initials: CM
authors.lastname: Murray
authors.forename: Douglas
authors.initials: D
authors.lastname: Ferguson
authors.forename: Robert V
authors.initials: RV
authors.lastname: Bundick
authors.forename: David K
authors.initials: DK
authors.lastname: Donald
authors.forename: Henrik
authors.initials: H
authors.lastname: Ekberg
mesh_terms: D000818:Animals; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000209:etiology; D016027:Heart Transplantation; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors*; D051381:Rats; D011917:Rats, Inbred Lew; D027981:Symporters / Q000037:antagonists & inhibitors*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D006571:Heterocyclic Compounds; D007166:Immunosuppressive Agents; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C525748:AR C117977