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) 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.
Hauske
J R
JR
Central Research Division, Pfizer Inc, Groton, Connecticut 06340.
Dorff
P
P
Julin
S
S
DiBrino
J
J
Spencer
R
R
Williams
R
R
D000591:Amino Acid Isomerases / Q000138:chemical synthesis / Q000494:pharmacology; D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000494:pharmacology; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology; D019696:Peptidylprolyl Isomerase; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D022021:Tacrolimus Binding Proteins
D000596:Amino Acids; D002352:Carrier Proteins; D007659:Ketones; D000591:Amino Acid Isomerases; D022021:Tacrolimus Binding Proteins; D019696:Peptidylprolyl Isomerase