Evaluation of amino acid-based linkers in potent macrocyclic inhibitors of farnesyl-protein transferase.
A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.
Beshore
D C
DC
Department of Medicinal Chemistry, Merck Research Laboratories, PA 19486, West Point, USA. douglas_beshore@merck.com
Bell
I M
IM
Dinsmore
C J
CJ
Homnick
C F
CF
Culberson
J C
JC
Robinson
R G
RG
Fernandes
C
C
Walsh
E S
ES
Abrams
M T
MT
Bhimnathwala
H G
HG
Davide
J P
JP
Ellis-Hutchings
M S
MS
Huber
H A
HA
Koblan
K S
KS
Buser
C A
CA
Kohl
N E
NE
Lobell
R B
RB
Chen
I W
IW
McLoughlin
D A
DA
Olah
T V
TV
Graham
S L
SL
Hartman
G D
GD
Williams
T M
TM
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006207:Half-Life; D020128:Inhibitory Concentration 50; D008657:Metabolic Clearance Rate / Q000502:physiology; D008968:Molecular Conformation; D011485:Protein Binding / Q000187:drug effects; D051381:Rats
D000596:Amino Acids; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase