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
The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-activity relationships and were able to decrease oxidative metabolism significantly. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Guanilil Ciclase Solúvel/metabolismo , Relação Estrutura-Atividade , Administração Intravenosa , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Técnicas de Química Sintética , Cães , Hepatócitos/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/administração & dosagem , Humanos , Masculino , NG-Nitroarginina Metil Éster/efeitos adversos , Pirimidinas/administração & dosagem , Ratos Transgênicos , Ratos Wistar , Guanilil Ciclase Solúvel/genéticaRESUMO
Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impairments of the NO-sGC signaling pathway have been implicated in the pathogenesis of cardiovascular and other diseases. Direct stimulation of sGC represents a promising therapeutic strategy particularly for the treatment of pulmonary hypertension (PH), a disabling disease associated with a poor prognosis. Previous sGC stimulators such as the pyrazolopyridines BAY 41-2272 and BAY 41-8543 demonstrated beneficial effects in experimental models of PH, but were associated with unfavorable drug metabolism and pharmacokinetic (DMPK) properties. Herein we disclose an extended SAR exploration of this compound class to address these issues. Our efforts led to the identification of the potent sGC stimulator riociguat, which exhibits an improved DMPK profile and exerts strong effects on pulmonary hemodynamics and exercise capacity in patients with PH. Riociguat is currently being investigated in phase III clinical trials for the oral treatment of PH.