A tacrolimus-related immunosuppressant with reduced toxicity

Transplantation
F J DumontM Wyvratt

Abstract

Tacrolimus (FK506) has potent immunosuppressive properties reflecting its ability to block the transcription of lymphokine genes in activated T cells through formation of a complex with FK506 binding protein-12, which inhibits the phosphatase activity of calcineurin. The clinical usefulness of tacrolimus is limited, however, by severe adverse effects, including neurotoxicity and nephrotoxicity. Although this toxicity, like immunosuppression, appears mechanistically related to the calcineurin inhibitory action of the drug, a large chemistry effort has been devoted to search for tacrolimus analogs with reduced toxicity but preserved immunosuppressive activity that might have enhanced therapeutic utility. Here, we report on the identification of such an analog, which was synthetically derived from ascomycin (ASC), the C21 ethyl analog of tacrolimus, by introducing an indole group at the C32 position. The profile of biological activity of indolyl-ASC was characterized in rodent models of immunosuppression and toxicity. Indolyl-ASC was found to exhibit an immunosuppressive potency equivalent to that of tacrolimus in T-cell activation in vitro and in murine transplant models, even though indolyl-ASC bound about 10 times less to intra...Continue Reading

References

May 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·D A FrumanS J Burakoff
Mar 1, 1992·Physiology & Behavior·R Refinetti, M Menaker
Feb 1, 1992·Kidney International·B J NankivellD C Harris
Oct 1, 1973·Physiological Reviews·H Hensel
Nov 1, 1981·Journal of Pharmacological Methods·M S MillerT F Burks
Jan 1, 1995·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·H Klinkmann, J Vienken
Apr 1, 1994·Annals of Neurology·E F WijdicksR A Krom
Aug 15, 1994·Transplantation·R M JindalC M Miller
May 14, 1993·Biochemical and Biophysical Research Communications·M AsamiC Tanaka
Jan 1, 1997·Annual Review of Immunology·A RaoP G Hogan

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Citations

Oct 25, 2001·Analytical Biochemistry·C W CarrerasD V Santi
Feb 23, 2002·Bioorganic & Medicinal Chemistry Letters·Bolin GengPeter V Pallai
Aug 18, 1999·Bioorganic & Medicinal Chemistry Letters·M T GouletW H Parsons
Aug 18, 1999·Bioorganic & Medicinal Chemistry Letters·H M ArmstrongW H Parsons
Dec 16, 2003·The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation·Mario StalderRandall E Morris
Jul 9, 2002·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·J KurtzM Sykes
Apr 27, 2001·Immunopharmacology and Immunotoxicology·P StrestíkováH Farghali
Oct 29, 2009·Cell Communication and Signaling : CCS·Matthias Sieber, Ria Baumgrass
Aug 12, 2014·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Carmen Freire-CoboGermán Sierra-Marcuño
Feb 27, 2008·International Reviews of Immunology·Jonghwa Won, Ge Hyeong Lee
Jan 27, 2018·International Journal of Molecular Sciences·Quincy A Quick
Feb 1, 2008·Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society·Ashokkumar JainAdel Bozorgzadeh
Nov 18, 1998·Current Opinion in Nephrology and Hypertension·J L Ader, L Rostaing
Jul 24, 1998·Archives of Biochemistry and Biophysics·S P Salowe, J D Hermes

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