3,8-Diazabicyclo[3.2.1]octan-2-one peptide mimetics: synthesis of a conformationally restricted inhibitor of farnesyltransferase.
A new synthesis of the 3,8-diazabicyclo[3.2.1]octan-2-one framework is described. Transannular enolate alkylation of piperazinone derivatives provides a flexible route to highly constrained bicyclic peptidomimetic synthons with substitution at the Calpha position. The chemistry was used to produce a conformationally constrained farnesyltransferase inhibitor, which aided the elucidation of enzyme-bound conformation.
Dinsmore
C J
CJ
Departments of Medicinal Chemistry, Molecular Systems, and Cancer Research, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA. christopher_dinsmore@merck.com
Bergman
J M
JM
Bogusky
M J
MJ
Culberson
J C
JC
Hamilton
K A
KA
Graham
S L
SL
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D051231:Farnesyltranstransferase; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D013816:Thermodynamics
C426408:3,8-diazabicyclo(3.2.1)octan-2-one; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010455:Peptides; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase