RESUMO
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
Assuntos
Regulação para Baixo/efeitos dos fármacos , Descoberta de Drogas , Neoplasias da Próstata/tratamento farmacológico , Piridazinas/farmacologia , Receptores Androgênicos/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Estrutura Molecular , Neoplasias da Próstata/patologia , Piridazinas/síntese química , Piridazinas/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.
Assuntos
Antineoplásicos/síntese química , Organofosfatos/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/síntese química , Quinazolinas/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Aurora Quinase A , Aurora Quinase B , Aurora Quinases , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores das Enzimas do Citocromo P-450 , Ensaios de Seleção de Medicamentos Antitumorais , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Feminino , Histonas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Organofosfatos/farmacocinética , Organofosfatos/farmacologia , Fosforilação , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Ligação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
Exploration of the structure-activity relationships of the traditional C-5 acetamidomethyl side chain of the oxazolidonone antibacterials has yielded new, potent series of compounds of which the first examples, the O-linked iosoxazoles are described in detail, leading to the selection of the pre-clinical candidate AZD2563.