Discovery and structure-activity relationships of imidazole-containing tetrahydrobenzodiazepine inhibitors of farnesyltransferase.
2,3,4,5-Tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepines were found to be potent inhibitors of farnesyltransferase (FT). A hydrophobic substituent at the 4-position of the benzodiazepine, linked via a hydrogen bond acceptor, was important to enzyme inhibitory activity. An aryl ring at position 7 or a hydrophobic group linked to the 8-position through an amide, carbamate, or urea linkage was also important for potent inhibition. 2,3,4, 5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-7-(4-pyridinyl)-4-[2-(t rifluo romethoxy)benzoyl]-1H-1,4-benzodiazepine (36), with an FT IC(50) value of 24 nM, produced 85% phenotypic reversion of Ras transformed NIH 3T3 cells at 1.25 microM and had an EC(50) of 160 nM for inhibition of anchorage-independent growth in soft agar of H-Ras transformed Rat-1 cells. Selected analogues demonstrated ip antitumor activity against an ip Rat-1 tumor in mice.
Ding
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Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Batorsky
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Bhide
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Chao
H J
HJ
Cho
Y
Y
Chong
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Gullo-Brown
J
J
Guo
P
P
Kim
S H
SH
Lee
F
F
Leftheris
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K
Miller
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A
Mitt
T
T
Patel
M
M
Penhallow
B A
BA
Ricca
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C
Rose
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WC
Schmidt
R
R
Slusarchyk
W A
WA
Vite
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Yan
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Manne
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Hunt
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JT
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology*; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D001569:Benzodiazepines; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase