Analogs of cyclosporin A modified at the D-Ala8 position.
The conversion of [2-deutero-3-fluoro-D-Ala8]cyclosporin A (1) to a dehydroalanine analog [delta-Ala8]cyclosporin A (2) was achieved with lithium diisopropylamide in THF at low temperature. This dehydro compound is a useful intermediate for the preparation of position 8 analogs of cyclosporin A formed from it by the conjugate addition of thiol compounds. NMR conformational studies have provided evidence for the restoration of D-stereochemistry in the modified Ala8 residues. The preparation of several of these cyclosporin analogs and their bioactivities are described.
Patchett
A A
AA
Merck, Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065.
Taub
D
D
Hensens
O D
OD
Goegelman
R T
RT
Yang
L
L
Dumont
F
F
Peterson
L
L
Sigal
N H
NH
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003524:Cyclosporins / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology; D008213:Lymphocyte Activation; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013601:T-Lymphocytes / Q000187:drug effects*
D003524:Cyclosporins; D007166:Immunosuppressive Agents