title: Discovery and structure-activity relationships of imidazole-containing tetrahydrobenzodiazepine inhibitors of farnesyltransferase.
abstract: 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.
authors.affiliation: Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
authors.forename: C Z
authors.initials: CZ
authors.lastname: Ding
authors.forename: R
authors.initials: R
authors.lastname: Batorsky
authors.forename: R
authors.initials: R
authors.lastname: Bhide
authors.forename: H J
authors.initials: HJ
authors.lastname: Chao
authors.forename: Y
authors.initials: Y
authors.lastname: Cho
authors.forename: S
authors.initials: S
authors.lastname: Chong
authors.forename: J
authors.initials: J
authors.lastname: Gullo-Brown
authors.forename: P
authors.initials: P
authors.lastname: Guo
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: F
authors.initials: F
authors.lastname: Lee
authors.forename: K
authors.initials: K
authors.lastname: Leftheris
authors.forename: A
authors.initials: A
authors.lastname: Miller
authors.forename: T
authors.initials: T
authors.lastname: Mitt
authors.forename: M
authors.initials: M
authors.lastname: Patel
authors.forename: B A
authors.initials: BA
authors.lastname: Penhallow
authors.forename: C
authors.initials: C
authors.lastname: Ricca
authors.forename: W C
authors.initials: WC
authors.lastname: Rose
authors.forename: R
authors.initials: R
authors.lastname: Schmidt
authors.forename: W A
authors.initials: WA
authors.lastname: Slusarchyk
authors.forename: G
authors.initials: G
authors.lastname: Vite
authors.forename: N
authors.initials: N
authors.lastname: Yan
authors.forename: V
authors.initials: V
authors.lastname: Manne
authors.forename: J T
authors.initials: JT
authors.lastname: Hunt
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D001569:Benzodiazepines; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase