RESUMO
An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.
Assuntos
Antineoplásicos/química , Benzamidas/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Compostos Macrocíclicos/química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Sítios de Ligação , Biomarcadores/metabolismo , Avaliação Pré-Clínica de Medicamentos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Estrutura Terciária de Proteína , Ratos , Transplante HeterólogoRESUMO
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activity at least 24h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth.
Assuntos
Aminas/síntese química , Benzamidas/síntese química , Biomarcadores Tumorais , Descoberta de Drogas , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Aminas/química , Aminas/farmacologia , Animais , Benzamidas/química , Benzamidas/farmacologia , Benzoquinonas/síntese química , Benzoquinonas/química , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Compostos Macrocíclicos/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias/tratamento farmacológico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.
Assuntos
Antineoplásicos/farmacologia , Biomarcadores/metabolismo , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Concentração Inibidora 50 , Lactamas Macrocíclicas/química , Modelos Moleculares , Estrutura Molecular , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologiaRESUMO
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.
Assuntos
Antineoplásicos/química , Benzamidas/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells.
Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/química , Piridinas/química , Pirimidinas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Pirazóis/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologiaRESUMO
We report the synthesis of the novel scaffolds pyrazino[1,2-b]isoquinoline and pyrrolo[1,2-a]pyrazine displaying the somatostatin pharmacophores. Both classes of compounds contain a pyrazine heterocycle, which can be prepared in a straightforward manner utilizing an intramolecular Fukuyama-Mitsunobu reaction. As both the families derive from amino acids, they can be accessed in high optical purity.