SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo.
BACKGROUND
This report describes the preclinical pharmacological profile of the new rapamycin analog, SDZ RAD, i.e., 40-O-(2-hydroxyethyl)-rapamycin.


METHODS
The pharmacological effects of SDZ RAD were assessed in a variety of in vitro and in vivo models, which included an autoimmune disease model as well as kidney and heart allotransplantation models using different rat strain combinations.


RESULTS
SDZ RAD has a mode of action that is different from that of cyclosporine or FK506. In contrast to the latter, SDZ RAD inhibits growth factor-driven cell proliferation in general, as demonstrated for the in vitro cell proliferation of a lymphoid cell line and of vascular smooth muscle cells. SDZ RAD is immunosuppressive in vitro as demonstrated by the inhibition of mouse and human mixed lymphocyte reactions and the inhibition of antigen-driven proliferation of human T-cell clones. The concentrations needed to achieve 50% inhibition in all of these assays fall into the subnanomolar range. SDZ RAD is effective in the in vivo models when given by the oral route in doses ranging between 1 mg/kg/day and 5 mg/kg/day. When compared with rapamycin, the in vitro activity of SDZ RAD is generally about two to three times lower; however, when administered orally, SDZ RAD is at least as active in vivo as rapamycin.


CONCLUSIONS
In conclusion, SDZ RAD is a new, orally active rapamycin-derivative that is immunosuppressive and that efficiently prevents graft rejection in rat models of allotransplantation. SDZ RAD has therefore been selected for development for use in combination with cyclosporine A to prevent acute and chronic rejection after solid organ allotransplantation.
Schuler
W
W
Preclinical Research, and Technical Research and Development, Novartis Pharma AG, Basel, Switzerland.
Sedrani
R
R
Cottens
S
S
Häberlin
B
B
Schulz
M
M
Schuurman
H J
HJ
Zenke
G
G
Zerwes
H G
HG
Schreier
M H
MH
D000005:Abdomen; D000284:Administration, Oral; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005921:Glomerulonephritis / Q000139:chemically induced; D006084:Graft Rejection / Q000517:prevention & control; D006087:Graft vs Host Reaction / Q000187:drug effects; D006131:Growth Inhibitors / Q000502:physiology; D006133:Growth Substances / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation; D008627:Mercuric Chloride; D011090:Polyenes / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D020123:Sirolimus / Q000031:analogs & derivatives; D022021:Tacrolimus Binding Proteins; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000276:immunology
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D006133:Growth Substances; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D011090:Polyenes; D008627:Mercuric Chloride; D000068338:Everolimus; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus