RESUMO
Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2-a]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28. It turned out that BAY 1165747 (BAY-747, 28) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 (28) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.
Assuntos
Guanilato Ciclase , Hipertensão , Humanos , Guanilil Ciclase Solúvel/metabolismo , Guanilato Ciclase/metabolismo , Hipertensão/tratamento farmacológico , Vasodilatadores , Piridinas/farmacologia , Piridinas/uso terapêutico , Óxido Nítrico/metabolismoRESUMO
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
Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano-1,4-dihydropyridines that were identified by high-throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94-8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phaseâ II trial.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Nefropatias/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/química , Naftiridinas/química , Receptores de Mineralocorticoides/química , Animais , Sítios de Ligação , Doença Crônica , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Insuficiência Cardíaca/complicações , Humanos , Nefropatias/complicações , Antagonistas de Receptores de Mineralocorticoides/síntese química , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Naftiridinas/síntese química , Naftiridinas/uso terapêutico , Potássio/urina , Estrutura Terciária de Proteína , Ratos , Receptores de Mineralocorticoides/metabolismo , Sódio/urinaRESUMO
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.