INHIBITORS OF CXCR1/2 AS ADJUVANTS IN THE TRANSPLANT OF PANCREATIC ISLETS
The invention relates to CXCR1 and/or CXCR2 inhibitors for the preparation of a medicament for use as an adjuvant in the transplant of pancreatic islets in Type 1 diabetes patients. In particular, the compounds that can be used according to the invention have the following formula (I) in which R and R′ are as defined in the description.
1 - 8 . (canceled)
9 . A method of reducing or inhibiting graft rejection in an individual having received a pancreatic islet cell transplant, the method comprising:
identifying an individual having Type 1 diabetes and having received a pancreatic islet cell transplant;
administering to the individual a medicament comprising an inhibitor of CXCR1 and/or CXCR2.
10 . The method of claim 9 , wherein the inhibitor of CXCR1 and/or CXCR2 is a compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein R 1 is linear or branched (C 1 -C 6 )alkyl and R is selected from the group consisting of linear or branched 4-(C 1 -C 6 )alkyl, 4-trifluoromethane-sulfonyloxy, and 3-benzoyl.
11 . The method of claim 10 , wherein the pharmaceutically acceptable salt is selected from the group consisting of lysine salts and sodium salts.
12 . The method of claim 10 , wherein the compound of formula I is selected from the group consisting of R(−)-N-2-[(4-isobutylphenyl)propionyl]-methanesulfonamide and R(+)-2-[(4′-trifluoromethanesulfonyloxy)phenyl]propionyl-methanesulfonamide.
13 . The method of claim 9 , wherein the medicament improves engraftment and/or early graft function of the transplanted pancreatic islet cells.
14 . The method of claim 9 , wherein the medicament reduces the occurrence of failure of the transplanted pancreatic islet cells.
15 . The method of claim 9 , wherein the medicament improves long term graft survival of the transplanted pancreatic islet cells.
16 . A method of improving graft survival and/or graft function in an individual having received a pancreatic islet cell transplant, the method comprising:
identifying an individual having Type 1 diabetes and having received a pancreatic islet cell transplant;
administering to the individual a medicament comprising an inhibitor of CXCR1 and/or CXCR2.
17 . The method of claim 16 , wherein the inhibitor of CXCR1 and/or CXCR2 is a compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein R 1 is linear or branched (C 1 -C 6 )alkyl and R is selected from the group consisting of linear or branched 4-(C 1 -C 6 ) alkyl, 4-trifluoromethane-sulfonyloxy, and 3-benzoyl.
18 . The method of claim 17 , wherein the pharmaceutically acceptable salt is selected from the group consisting of lysine salts and sodium salts.
19 . The method of claim 17 , wherein the compound of formula I is selected from the group consisting of R(−)-N-2-[(4-isobutylphenyl)propionyl]-methanesulfonamide and R(−)-2-[(4′-trifluoromethanesulfonyloxy)phenyl]propionyl-methanesulfonamide.
20 . The method of claim 16 , wherein the medicament reduces or inhibits graft rejection in the individual having received the pancreatic islet cell transplant.
21 . The method of claim 16 , wherein the medicament reduces the occurrence of failure of the transplanted pancreatic islet cells.
22 . The method of claim 16 , wherein the medicament improves long term graft survival of the transplanted pancreatic islet cells.
23 . A method of treating an individual having received a pancreatic islet cell transplant, the method comprising:
identifying an individual having Type 1 diabetes and having received a pancreatic islet cell transplant;
administering to the individual a medicament comprising a compound effective to inhibit CXCL8 biological activity derived from CXCR1 and/or CXCR2 activation.
24 . The method of claim 23 , wherein the compound effective to inhibit CXCL8 biological activity derived from CXCR1 and/or CXCR2 activation is a compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein R 1 is linear or branched (C 1 -C 6 )alkyl and R is selected from the group consisting of linear or branched 4-(C 1 -C 6 )alkyl, 4-trifluoromethane-sulfonyloxy, and 3-benzoyl.
25 . The method of claim 24 , wherein the pharmaceutically acceptable salt is selected from the group consisting of lysine salts and sodium salts.
26 . The method of claim 24 , wherein the compound of formula I is selected from the group consisting of R(−)-N-2-[(4-isobutylphenyl)propionyl]-methanesulfonamide and R(+)-2-[(4′-trifluoromethanesulfonyloxy)phenyl]propionyl-methanesulfonamide.
27 . The method of claim 23 wherein the medicament reduces or inhibits graft rejection in the individual having received the pancreatic islet cell transplant.
28 . The method of claim 23 , wherein the medicament reduces the occurrence of failure of the transplanted pancreatic islet cells.