RESUMO
This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.
Assuntos
Antineoplásicos/química , Benzimidazóis/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Aurora Quinases , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Linhagem Celular Tumoral , Humanos , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
(+)-1,4-Dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid (voreloxin; formerly SNS-595 or AG-7352) is currently under investigation for the treatment of platinum-resistant ovarian cancer and acute myeloid leukemia. In vitro voreloxin undergoes minimal cytochrome P450 (P450) and UDP glucuronosyltransferase (UGT)-mediated metabolism, and in vivo excretion of unchanged voreloxin as the major species is consistent with the slow rate of metabolism observed in vitro. The objective of the present study was to examine the cross-species metabolic profile of voreloxin and to identify and characterize the metabolites formed in rats. We also investigated baculovirus-expressed human P450s and UGTs to determine which isoforms participated in voreloxin metabolism. Incubations using human, monkey, and rat liver microsomes showed monkey and rat metabolism is similar to human. Voreloxin and metabolites collected from plasma, bile, and urine from rats administered radiolabeled voreloxin were separated by high-performance liquid chromatography, and their structures were elucidated by liquid chromatography/tandem mass spectrometry. Activity of metabolites was determined with authentic reference standards in cell-based cytotoxicity assays. The proposed structures of metabolites suggest that metabolic pathways for voreloxin include glucuronide conjugation, oxidation, N-dealkylation, and O-dealkylation.
Assuntos
Dano ao DNA , Replicação do DNA/efeitos dos fármacos , Naftiridinas/metabolismo , Tiazóis/metabolismo , Animais , Área Sob a Curva , Bile/metabolismo , Cromatografia Líquida de Alta Pressão , Masculino , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.
Assuntos
Neoplasias Experimentais/tratamento farmacológico , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Quinazolinas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinases , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/enzimologia , Quinazolinas/química , Relação Estrutura-AtividadeRESUMO
We have identified a small-molecule inhibitor of tumor necrosis factor alpha (TNF-alpha) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-alpha activity in biochemical and cell-based assays with median inhibitory concentrations of 22 and 4.6 micromolar, respectively. Formation of an intermediate complex between the compound and the intact trimer results in a 600-fold accelerated subunit dissociation rate that leads to trimer dissociation. A structure solved by x-ray crystallography reveals that a single compound molecule displaces a subunit of the trimer to form a complex with a dimer of TNF-alpha subunits.