title: C32-O-imidazol-2-yl-methyl ether derivatives of the immunosuppressant ascomycin with improved therapeutic potential.
abstract: A series of C32-O-aralkyl ether derivatives of the FK-506 related macrolide ascomycin have been prepared based on an earlier reported C32-O-cinnamyl ether design. In the present study, the nature of the aryl tethering group was varied in an attempt to improve oral activity. An imidazol-2-yl-methyl tether was found to be superior among those investigated and has resulted in an ascomycin analog, L-733,725, with in vivo immunosuppressive activity comparable to FK-506 but with an improved therapeutic index.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Goulet
authors.forename: S R
authors.initials: SR
authors.lastname: McAlpine
authors.forename: M J
authors.initials: MJ
authors.lastname: Staruch
authors.forename: S
authors.initials: S
authors.lastname: Koprak
authors.forename: F J
authors.initials: FJ
authors.lastname: Dumont
authors.forename: J G
authors.initials: JG
authors.lastname: Cryan
authors.forename: G J
authors.initials: GJ
authors.lastname: Wiederrecht
authors.forename: R
authors.initials: R
authors.lastname: Rosa
authors.forename: M B
authors.initials: MB
authors.lastname: Wilusz
authors.forename: L B
authors.initials: LB
authors.lastname: Peterson
authors.forename: M J
authors.initials: MJ
authors.lastname: Wyvratt
authors.forename: W H
authors.initials: WH
authors.lastname: Parsons
mesh_terms: D000818:Animals; D001682:Biological Availability; D007035:Hypothermia / Q000139:chemically induced; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D020104:Immunophilins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D007202:Indicators and Reagents; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D015394:Molecular Structure; D009498:Neurotoxins / Q000633:toxicity; D051381:Rats; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D022021:Tacrolimus Binding Proteins
chemical_list: D007093:Imidazoles; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; C116704:L 733725; D009498:Neurotoxins; C058028:immunomycin; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D016559:Tacrolimus