- Design and synthesis of piperidine farnesyltransferase inhibitors with reduced glucuronidation potential
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The design and synthesis of a novel piperidine series of farnesyltransferase (FTase) inhibitors with reduced potential for metabolic glucuronidation are described. The various substitution and exchange of the phenyl group at the C-2 position of the previously described 2-(4-hydroxy)phenyl-3-nitropiperidine 1a (FTase IC50 = 5.4 nM) resulted in metabolically stable compounds with potent FTase inhibition (14a IC50 = 4.3 nM, 20a IC50 = 3.0 nM, and 50a IC50 = 16 nM). Molecular modeling studies of these compounds complexed with FTase and farnesyl pyrophosphate are also described.
- Tanaka, Rieko,Rubio, Almudena,Harn, Nancy K.,Gernert, Douglas,Grese, Timothy A.,Eishima, Jun,Hara, Mitsunobu,Yoda, Nobuyuki,Ohashi, Rui,Kuwabara, Takashi,Soga, Shiro,Akinaga, Shiro,Nara, Shinji,Kanda, Yutaka
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p. 1363 - 1382
(2008/02/13)
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- Novel N-(4-piperidinyl)benzamide antimalarials with mammalian protein farnesyltransferase inhibitory activity
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Protein farnesyltransferase of Plasmodium falciparum is a potential target in the treatment of malaria for which increased drug resistance is observed. The design, synthesis and evaluation of a series of N-(4-piperidinyl)benzamides is reported. The most potent compounds showed in vitro activity against the parasite at submicromolar concentrations.
- Ryckebusch, Adina,Gilleron, Pauline,Millet, Regis,Houssin, Raymond,Lemoine, Amelie,Pommery, Nicole,Grellier, Philippe,Sergheraert, Christian,Henichart, Jean-Pierre
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p. 1324 - 1326
(2007/10/03)
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- Potent and selective farnesyl transferase inhibitors
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We recently described a novel series of CA1A2X peptidomimetics as farnesyl transferase inhibitors (FTIs). These compounds possess an N-(4-piperidinyl)benzamide scaffold mimicking A1A 2 residue. Extensive exploration of structure-activity relationships revealed that replacement of cysteine by substituted benzylimidazoles provided nanomolar FTIs with in vitro activities (18e, IC50 = 4.60 nM on isolated enzyme, EC50 = 20.0 nM for growth inhibition on a tumor cell line). The molecular docking of 18e and 19e in the active site of the enzyme provided details of key interactions with the protein and showed that the methionine or phenylalanine residue fits into the aryl binding site.
- Millet, Régis,Domarkas, Juozas,Houssin, Raymond,Gilleron, Pauline,Goossens, Jean-Fran?ois,Chavatte, Philippe,Logé, Cédric,Pommery, Nicole,Pommery, Jean,Hénichart, Jean-Pierre
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p. 6812 - 6820
(2007/10/03)
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- Method of treating cancer
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The present invention relates to methods of treating cancer using a combination of a compound which is a PSA conjugate and a compound which is a inhibitor of prenyl-protein transferase, which methods comprise administering to said mammal, either sequentially in any order or simultaneously, amounts of at least two therapeutic agents selected from a group consisting of a compound which is a PSA conjugate and a compound which is a inhibitor of prenyl-protein transferase. The invention also relates to methods of preparing such compositions.
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- INHIBITORS OF PRENYL-PROTEIN TRANSFERASE
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The present invention is directed to peptidomimetic piperazine-containing macrocyclic compounds which inhibit prenyl-protein transferase and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras
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- Inhibitors of prenyl-protein transferase
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The present invention comprises piperazinone-containing compounds which inhibit prenyl-protein transferases, including famesyl-protein transferase and geranylgeranyl-protein transferase type I. Such therapeutic compounds are useful in the treatment of cancer.
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- Inhibitors of prenyl-protein transferase
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The present invention comprises piperazinone-containing compounds, which may be useful as inhibitors of prenyl-protein transferases, including farnesyl-protein transferase and geranylgeranyl-protein transferase type I. Such therapeutic compounds are useful in the treatment of cancer.
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- Inhibitors of prenyl-protein transferase
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The present invention is directed to macrocyclic compounds which inhibit prenyl-protein transferase and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- Inhibitors of prenyl-protein transferase
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The present invention is directed to peptidomimetic macrocyclic compounds which inhibit prenyl-protein transferase and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds
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- Inhibitors of prenyl-protein transferase
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The present invention is directed to macrocyclic compounds which inhibit prenyl-protein transferase (FTase) and the prenylation of the oncogene protein Ras. The invention is further directed to chemothera-peutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.
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- Substituted phenyl farnesyltransferase inhibitors
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Compounds of formula (I) or pharmaceutically acceptable salts thereof, inhibit farnesyltransferase. Methods for making the compounds, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds are disclosed.
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- Inhibitors of prenyl-protein transferase
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The present invention comprises piperazine-containing compounds which inhibit prenyl-protein transferases, including farnesyl-protein transferase and geranylgeranyl-protein transferase type I. Such therapeutic compounds are useful in the treatment of canc
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- Inhibitors of prenyl-protein transferase
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The present invention comprises piperazine-containing compounds which inhibit prenyl-protein transferases, including farnesyl-protein transferase and geranylgeranyl-protein transferase type I. Such therapeutic compounds are useful in the treatment of canc
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- Inhibitors of prenyl-protein transferase
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The present invention is directed to peptidomimetic macrocyclic compounds which inhibit prenyl-protein transferase and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.
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- INHIBITORS OF PRENYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit prenyl-protein transferases, farnesyl-protein transferase and geranylgeranyl-protein transferase type I, and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and geranylgeranyl-protein transferase type I and the prenylation of the oncogene protein RAS.
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- Inhibitors of prenyl-protein transferase
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The present invention is directed to compounds which inhibit a prenyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting a prenyl-protein transferase and the prenylation of the oncogene protein Ras.
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- Inhibitors of prenyl-protein transferase
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The present invention is directed to peptidomimetic piperazine-containing macrocyclic compounds which inhibit a prenyl-protein transferase (FTase) and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.
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- Inhibitors of farnesyl-protein transferase
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- Inhibitors of farnesyl-protein transferase
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- Inhibitors of farnesyl-protein transferase
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- Radiolabeled farnesyl-protein transferase inhibitors
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The present invention is directed toward radiolabeled farnesyl-protein transferase inhibitor compounds which are useful to label FPTase in assays, whether cell-based, tissue-based or in whole animal. The tracers can also be used in competitive binding assays to obtain information on the interaction of unlabeled FTIs with FPTase.
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- Inhibitors of prenyl-protein transferase
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The present invention is directed to compounds which inhibit prenyl-protein transferase (FTase) and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.
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- Substituted imidazole compounds useful as farnesyl-protein transferase inhibitors
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PCT No. PCT/US97/06257 Sec. 371 Date Oct. 2, 1998 Sec. 102(e) Date Oct. 2, 1998 PCT Filed Apr. 1, 1997 PCT Pub. No. WO97/36876 PCT Pub. Date Oct. 9, 1997The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
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- Inhibitors of farnesyl-protein transferase
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PCT No. PCT/US97/01600 Sec. 371 Date Jul. 27, 1998 Sec. 102(e) Date Jul. 27, 1998 PCT Filed Jan. 27, 1997 PCT Pub. No. WO97/27854 PCT Pub. Date Aug. 7, 1997The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) a
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- Imidazole-containing diarylether and diarylsulfone inhibitors of farnesyl-protein transferase
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The design and syntheses of non-thiol inhibitors of farnesyl-protein transferase are described. Optimization of cysteine-substituted diarylethers led to highly potent imidazole-containing diarylethers and diarylsulfones. Polar diaryl linkers dramatically
- Dinsmore, Christopher J.,Williams, Theresa M.,O'Neill, Timothy J.,Liu, Dongming,Rands, Elaine,Culberson, J. Christopher,Lobell, Robert B.,Koblan, Kenneth S.,Kohl, Nancy E.,Gibbs, Jackson B.,Oliff, Allen I.,Graham, Samuel L.,Hartman, George D.
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p. 3301 - 3306
(2007/10/03)
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to piperazine-2,3-dione compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- Inhibitors of farnesyl-protein transferase
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras
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- Arylheteroaryl inhibitors of farnesyl-protein transferase
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The present invention is directed to compounds which inhibit famesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting famesyl-protein transferase and the famesyl of the oncogene protein Ras.
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- Inhibitors of farnesyl-protein transferase
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- Biheteroaryl inhibitors of farnesyl-protein transferase
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The present invention is directed to compounds of the formula A which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras: STR1 The invention is further directed to chemotherapeutic compositions containing the co
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras
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- Inhibitors of farnesyl-protein transferase
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- BISPHENYL INHIBITORS OF FARNESYLPROTEIN TRANSFERASE
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The present invention comprises peptidomimetic compounds which comprise a suitably substituted aminoalkylbenzene and analine analogs, further substituted with a second phenyl ring attached via a bond, a heteroatom linker or an aliphatic linker. The instant compounds inhibit the farnesyl-protein transferase enzyme and the farnesylation of certain proteins. Furthermore, the instant farnesyl protein transferase inhibitors differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention comprises low molecular weight peptidyl compounds that inhibit the farnesyl-protein transferase. Furthermore, these compounds differ from the mono- or dipeptidyl analogs previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to substituted benozdiazepine compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
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- INHIBlTORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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