Aryl tetrahydropyridine inhibitors of farnesyltransferase: glycine, phenylalanine and histidine derivatives.
Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered a series of aryl tetrahydropyridines that incorporate substituted glycine, phenylalanine and histidine residues. The design, synthesis, SAR and biological properties of these compounds will be discussed.
Gwaltney
Stephen L
SL
Pharmaceutical Discovery, R47B, Building AP-10, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. stephen.gwaltney@syrrx.com
O'Connor
Stephen J
SJ
Nelson
Lissa T J
LT
Sullivan
Gerard M
GM
Imade
Hovis
H
Wang
Weibo
W
Hasvold
Lisa
L
Li
Qun
Q
Cohen
Jerome
J
Gu
Wen-Zhen
WZ
Tahir
Stephen K
SK
Bauch
Joy
J
Marsh
Kennan
K
Ng
Shi-Chung
SC
Frost
David J
DJ
Zhang
Haiying
H
Muchmore
Steve
S
Jakob
Clarissa G
CG
Stoll
Vincent
V
Hutchins
Charles
C
Rosenberg
Saul H
SH
Sham
Hing L
HL
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D011905:Genes, ras / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006639:Histidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011725:Pyridines; D010649:Phenylalanine; D006639:Histidine; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D005998:Glycine