5-Imidazolyl-quinolinones, -quinazolinones and -benzo-azepinones as farnesyltransferase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 9, 2003, Pages 1543-1547

  Angibaud, Patrick ^a   Bourdrez, Xavier ^a   Devine, Ann ^b   End, David W ^b   Freyne, Eddy ^c   Ligny, Yannick ^a   Muller, Philippe ^a   Mannens, Geert ^c   Pilatte, Isabelle ^a   Poncelet, Virginie ^a   Skrzat, Stacy ^b   Smets, Gerda ^c   Van Dun, Jacky ^c   Van Remoortere, Pieter ^c   Venet, Marc ^a,c   Wouters, Walter ^c  

^a Medicinal Chemistry Department   (France)

^b Drug Discovery   (United States)

^c NONE

Author keywords

[No Author keywords available]

Indexed keywords

ISOPROTEIN; PROTEIN FARNESYLTRANSFERASE INHIBITOR; QUINAZOLINE DERIVATIVE; QUINOLINE DERIVATIVE; TIPIFARNIB;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CHEMICAL MODIFICATION; CONTROLLED STUDY; DRUG POTENCY; DRUG SCREENING; DRUG SOLUBILITY; ENZYME ACTIVITY; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION;

EID: 12444338814     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00180-X     Document Type: Article

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26. 50 (cells): The concentration required to decrease the cell number by 50% as compared to a control (untreated) sample.
27. 3OH). Two pure fraction groups were collected and the solvent was evaporated. The first fraction was crystallized from 2-propanol/DIPE. The precipitate was filtered off and dried, yielding 4.4 g of (-)-8-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-6-(3- chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one 18a. The solvent of the second fraction group was evaporated. The second fraction was crystallized from 2-propanol/ DIPE. The precipitate was filtered off and dried, yielding: 4.1 g of (+)-8-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-6-(3- chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one 18b.
28. Metabolism: Compounds were incubated at 30 μM with human subcellular liver fractions (12,000 g supernatants) during 120 min at a final microsomal protein concentration of 1 mg/mL in a presence of an NADPH-generating system. Reactions were stopped by freezing the incubates in dry ice, and samples were stored at <18°C until analysis. Samples were analysed for unchanged compounds by HPLC-UV. The compounds were also incubated with boiled 12,000 g fractions to check the compound stability and recovery.
29. 2 asphyxiation. Tumors were excised, weighted, and fixed immediately in 4% paraformaldehyde. ANOVA, mean values for treatment groups, and SE for in vivo parameters were calculated on a VAX computer using IMSL subroutines compiled by the Science Information Department of the R.W. Johnson Pharmaceutical Research Institute. A value of p<0.05 was considered significant.
30. Meyer, C. Unpublished results.