Design and synthesis of novel FKBP inhibitors

Small molecule FKBP inhibitors were prepared with inhibitory activity ranging from micromolar to nanomolar. The design of these inhibitors derives from a structural analysis of the substrates for FKBP and cyclophilin. As a consequence of this analysis two key observations were made, namely: (1) amin...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1992-11, Vol.35 (23), p.4284-4296
Main Authors: Hauske, James R, Dorff, Peter, Julin, Susan, DiBrino, Joseph, Spencer, Robin, Williams, Rebecca
Format: Article
Language:English
Subjects:
Amino Acid Isomerases - chemical synthesis
Amino Acid Isomerases - pharmacology
Amino Acids - chemical synthesis
Amino Acids - pharmacology
Carrier Proteins - antagonists & inhibitors
Carrier Proteins - chemical synthesis
Carrier Proteins - pharmacology
Chemistry
Exact sciences and technology
Ketones - chemical synthesis
Ketones - pharmacology
Organic chemistry
Peptides
Peptidylprolyl Isomerase
Preparations and properties
Stereoisomerism
Structure-Activity Relationship
Tacrolimus Binding Proteins
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Description
Summary:Small molecule FKBP inhibitors were prepared with inhibitory activity ranging from micromolar to nanomolar. The design of these inhibitors derives from a structural analysis of the substrates for FKBP and cyclophilin. As a consequence of this analysis two key observations were made, namely: (1) amino ketone moieties are suitable as FKBP recognition elements at the P1-P1' site and (2) the P3'-P4' site will accept a trans-olefin as a suitable mimetic of a peptide moiety. The preparation of these non-peptide inhibitors is readily accomplished by a protocol which includes the synthesis of chiral propargylic amines and their subsequent conversion into vinyl zirconium reagents.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00101a005