RESUMO
Inhibition of monopolar spindle 1 (MPS1) kinase represents a novel approach to cancer treatment: instead of arresting the cell cycle in tumor cells, cells are driven into mitosis irrespective of DNA damage and unattached/misattached chromosomes, resulting in aneuploidy and cell death. Starting points for our optimization efforts with the goal to identify MPS1 inhibitors were two HTS hits from the distinct chemical series "triazolopyridines" and "imidazopyrazines". The major initial issue of the triazolopyridine series was the moderate potency of the HTS hits. The imidazopyrazine series displayed more than 10-fold higher potencies; however, in the early project phase, this series suffered from poor metabolic stability. Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 1217389 and reveal how both clinical candidates bind to the ATP site of MPS1 kinase, while addressing different pockets utilizing different binding interactions, along with their synthesis and preclinical characterization in selected in vivo efficacy models.
Assuntos
Antineoplásicos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Fuso Acromático/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Cães , Feminino , Células HT29 , Células HeLa , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/fisiologia , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/antagonistas & inibidores , Ratos , Ratos Wistar , Fuso Acromático/metabolismo , Resultado do TratamentoRESUMO
Wafers with varying concentrations of diphenhydramine hydrochloride (DPH-HCl) as active pharmaceutical ingredient (API) were prepared and their near infrared (NIR) and Raman spectra recorded. The purpose of this study was to compare the suitability of these two vibrational spectroscopic techniques for the quantification of DPH-HCl in pharmaceutical wafers. Partial least squares (PLS1) calibration models with different data pretreatments were tested. Both NIR and Raman spectroscopy proved to be suitable to predict DPH-HCl contents at lower concentration ranges. At higher concentrations, interference by crystallization processes was observed. For investigating the general applicability of the quantification methods, two commercially available products were examined.