RESUMO
Continuing structure-activity studies were performed on the 2,3,4, 5-tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepine farnesyltransferase (FT) inhibitors. These studies demonstrated that a 3(R)-phenylmethyl group, a hydrophilic 7-cyano group, and a 4-sulfonyl group bearing a variety of substituents provide low-nanomolar FT inhibitors with cellular activity at concentrations below 100 nM. Maximal in vivo activity in the mutated K-Ras bearing HCT-116 human colon tumor model was achieved with analogues carrying hydrophobic side chains such as propyl, phenyl, or thienyl attached to the N-4 sulfonyl group. Several such compounds achieved curative efficacy when given orally in this model. On the basis of its excellent preclinical antitumor activity and promising pharmacokinetics, compound 20 (BMS-214662, (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thie nyl sulfonyl)-1H-1,4-benzodiazepine) has been advanced into human clinical trials.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/síntese química , Benzodiazepinas/síntese química , Inibidores Enzimáticos/síntese química , Imidazóis/síntese química , Células 3T3 , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacocinética , Benzodiazepinas/farmacologia , Disponibilidade Biológica , Linhagem Celular Transformada , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase , Genes ras , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Células 3T3 , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Transformada , Farnesiltranstransferase , Ligação de Hidrogênio , Imidazóis/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Ratos , Relação Estrutura-AtividadeRESUMO
The syntheses of the enantiomeric cyclobutyl guanine nucleoside analogues [1R-1 alpha, 2 beta, 3 alpha]- and [1S-1 alpha, 2 beta, 3 alpha]-2- amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6H-purin-6-one (7 and 8, respectively) and the enantiomeric cyclobutyl adenine analogues [1R-1 alpha, 2 beta, 3 alpha]- and [1S-1 alpha, 2 beta, 3 alpha]-6-amino-9-[2,3-bis(hydroxymethyl) cyclobutyl]purine (9 and 10, respectively) are described. trans-3,3-Diethoxy-1,2-cyclobutanedicarboxylic acid (14) was coupled with R-(-)-2-phenylglycinol to provide a mixture of diastereomeric bis-amides, 15a and 15b, which was readily separated by crystallization. Conversion of each bis-amide to the corresponding diol enantiomer, 16a and 16b, respectively, was effected by a facile three-step sequence in high overall yield. Homochiral diol 16a was converted in a straightforward manner to 7 and 9, and homochiral diol 16b was similarly converted to the corresponding optical isomers 8 and 10. Compounds 7 and 9, which mimic the absolute configuration of natural nucleosides, are highly active against a range of herpesviruses in vitro while the isomers of opposite configuration, 8 and 10, are devoid of antiherpes activity. The corresponding triphosphates of 7 and 8 (7-TP and 8-TP) were prepared enzymatically. Compound 7-TP selectively inhibits HSV-1 DNA polymerase, compared to human (HeLa) DNA polymerase, while 8-TP is much less inhibitory than 7-TP against both types of enzymes. Compounds 7 and 9 are efficacious in a mouse cytomegalovirus model infection.