32-Ascomycinyloxyacetic acid derived immunosuppressants. Independence of immunophilin binding and immunosuppressive potency.
The potent immunosuppressant ascomycin (1b) was selectively alkylated at the C-32 carbinol, thus providing esters and amides of 32-ascomycinyloxyacetic acid (4, AOAA). These compounds present structural variation at the FKBP/calcineurin interface. While the native carboxylic acid 4 shows no activity in vitro, esters and simple amides of 4 exhibit potent immunosuppression in the human MLR assay. Moreover, amides show inhibitory activity in the rat popliteal lymph node hyperplasia assay. Surprisingly, FKBP binding was weakened by several orders of magnitude when secondary hydrophobic aryl amides of 4 were tested, while maintaining potent immunosuppressive efficacy in vitro.
Wagner
R
R
Abbott Laboratories, Pharmaceutical Products Division, Abbott Park, Illinois 60064, USA.
Rhoades
T A
TA
Or
Y S
YS
Lane
B C
BC
Hsieh
G
G
Mollison
K W
KW
Luly
J R
JR
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins
C112418:32-ascomycinyloxyacetic acid; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; C058028:immunomycin; D019703:Calcineurin; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus