Macrocyclic piperazinones as potent dual inhibitors of farnesyltransferase and geranylgeranyltransferase-I.
A series of macrocyclic piperazinone compounds with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to be potent inhibitors of protein prenylation in cell culture. A hypothesis for the binding mode of compound 3o in FPTase is proposed.
Dinsmore
Christopher J
CJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. christopher_dinsmore@merck.com
Zartman
C Blair
CB
Bergman
Jeffrey M
JM
Abrams
Marc T
MT
Buser
Carolyn A
CA
Culberson
J Christopher
JC
Davide
Joseph P
JP
Ellis-Hutchings
Michelle
M
Fernandes
Christine
C
Graham
Samuel L
SL
Hartman
George D
GD
Huber
Hans E
HE
Lobell
Robert B
RB
Mosser
Scott D
SD
Robinson
Ronald G
RG
Williams
Theresa M
TM
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D017368:Protein Prenylation; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology
D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D010879:Piperazines; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase