ABSTRACT
Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.
Subject(s)
Factor XIa , Fibrinolytic Agents , AnticoagulantsABSTRACT
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.
Subject(s)
Heart Failure/drug therapy , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Soluble Guanylyl Cyclase/metabolism , Structure-Activity Relationship , Administration, Intravenous , Administration, Oral , Animals , Blood Pressure/drug effects , Chemistry Techniques, Synthetic , Dogs , Hepatocytes/drug effects , Heterocyclic Compounds, 2-Ring/administration & dosage , Humans , Male , NG-Nitroarginine Methyl Ester/adverse effects , Pyrimidines/administration & dosage , Rats, Transgenic , Rats, Wistar , Soluble Guanylyl Cyclase/geneticsABSTRACT
The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery.
Subject(s)
Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/chemistry , Administration, Oral , Animals , Bile Acids and Salts/chemistry , Biological Availability , Biopharmaceutics/methods , Caco-2 Cells , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Humans , Lecithins/chemistry , Permeability , Pharmaceutical Preparations/metabolism , Rats , Solubility , Tablets/administration & dosage , Tablets/chemistry , Tablets/pharmacokineticsABSTRACT
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.
Subject(s)
Heart Failure/drug therapy , Kidney Diseases/drug therapy , Mineralocorticoid Receptor Antagonists/chemistry , Naphthyridines/chemistry , Receptors, Mineralocorticoid/chemistry , Animals , Binding Sites , Chronic Disease , Computer Simulation , Drug Evaluation, Preclinical , Heart Failure/complications , Humans , Kidney Diseases/complications , Mineralocorticoid Receptor Antagonists/chemical synthesis , Mineralocorticoid Receptor Antagonists/therapeutic use , Naphthyridines/chemical synthesis , Naphthyridines/therapeutic use , Potassium/urine , Protein Structure, Tertiary , Rats , Receptors, Mineralocorticoid/metabolism , Sodium/urineABSTRACT
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.