32-Ascomycinyloxyacetic acid derived immunosuppressants. Independence of immunophilin binding and immunosuppressive potency

J Med Chem. 1998 May 21;41(11):1764-76. doi: 10.1021/jm960066y.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Calcineurin / metabolism
  • Carrier Proteins / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Hyperplasia
  • Immunosuppressive Agents / chemical synthesis
  • Immunosuppressive Agents / chemistry
  • Immunosuppressive Agents / metabolism
  • Immunosuppressive Agents / pharmacology*
  • Lymph Nodes / drug effects
  • Lymph Nodes / pathology
  • Lymphocyte Culture Test, Mixed
  • Rats
  • Rats, Inbred Lew
  • Structure-Activity Relationship
  • Tacrolimus / analogs & derivatives*
  • Tacrolimus / chemical synthesis
  • Tacrolimus / chemistry
  • Tacrolimus / metabolism
  • Tacrolimus / pharmacology
  • Tacrolimus Binding Proteins

Substances

  • 32-ascomycinyloxyacetic acid
  • Carrier Proteins
  • DNA-Binding Proteins
  • Heat-Shock Proteins
  • Immunosuppressive Agents
  • immunomycin
  • Calcineurin
  • Tacrolimus Binding Proteins
  • Tacrolimus