Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders.

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.

BAY-7081: A Potent, Selective, and Orally Bioavailable Cyanopyridone-Based PDE9A Inhibitor.

Despite advances in the treatment of heart failure in recent years, options for patients are still limited and the disease is associated with considerable morbidity and mortality. Modulating cyclic guanosine monophosphate levels within the natriuretic peptide signaling pathway by inhibiting PDE9A has been associated with beneficial effects in preclinical heart failure models. We herein report the identification of BAY-7081, a potent, selective, and orally bioavailable PDE9A inhibitor with very good aqueous solubility starting from a high-throughput screening hit. Key aspect of the optimization was a switch in metabolism of our lead structures from glucuronidation to oxidation. The switch proved being essential for the identification of compounds with improved pharmacokinetic profiles. By studying a tool compound in a transverse aortic constriction mouse model, we were able to substantiate the relevance of PDE9A inhibition in heart diseases.

Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042).

Herein we describe the discovery, mode of action, and preclinical characterization of the soluble guanylate cyclase (sGC) activator runcaciguat. The sGC enzyme, via the formation of cyclic guanosine monophoshphate, is a key regulator of body and tissue homeostasis. sGC activators with their unique mode of action are activating the oxidized and heme-free and therefore NO-unresponsive form of sGC, which is formed under oxidative stress. The first generation of sGC activators like cinaciguat or ataciguat exhibited limitations and were discontinued. We overcame limitations of first-generation sGC activators and identified a new chemical class via high-throughput screening. The investigation of the structure-activity relationship allowed to improve potency and multiple solubility, permeability, metabolism, and drug-drug interactions parameters. This program resulted in the discovery of the oral sGC activator runcaciguat (compound 45, BAY 1101042). Runcaciguat is currently investigated in clinical phase 2 studies for the treatment of patients with chronic kidney disease and nonproliferative diabetic retinopathy.

Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure.

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.

Predicting biopharmaceutical performance of oral drug candidates - Extending the volume to dissolve applied dose concept.

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.

Identification of acidic heterocycle-substituted 1H-pyrazolo[3,4-b]pyridines as soluble guanylate cyclase stimulators.

Novel guanylate cyclase stimulators are disclosed. Design, synthesis, SAR, and pharmacological profile of the compounds are discussed.

Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases.

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 phase II trial.

Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension.

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.

Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor.

Despite recent progress in antithrombotic therapy, there is still an unmet medical need for safe and orally available anticoagulants. The coagulation enzyme Factor Xa (FXa) is a particularly promising target, and recent efforts in this field have focused on the identification of small-molecule inhibitors with good oral bioavailability. We identified oxazolidinone derivatives as a new class of potent FXa inhibitors. Lead optimization led to the discovery of BAY 59-7939 (5), a highly potent and selective, direct FXa inhibitor with excellent in vivo antithrombotic activity. The X-ray crystal structure of 5 in complex with human FXa clarified the binding mode and the stringent requirements for high affinity. The interaction of the neutral ligand chlorothiophene in the S1 subsite allows for the combination of good oral bioavailability and high potency for nonbasic 5. Compound 5 is currently under clinical development for the prevention and treatment of thromboembolic diseases.

Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids.

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease. Only interferon-alpha and the nucleosidic inhibitors of the viral polymerase, 3TC and adefovir, are approved for therapy. However, these therapies are limited by the side effects of interferon and the substantial resistance of the virus to nucleosidic inhibitors. Potent new antiviral compounds suitable for monotherapy or combination therapy are highly desired. We describe non-nucleosidic inhibitors of HBV nucleocapsid maturation that possess in vitro and in vivo antiviral activity. These inhibitors have potential for future therapeutic regimens to combat chronic HBV infection.

Substituted uracil derivatives as potent inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1).

A new class of PARP-1 inhibitors, namely substituted fused uracil derivatives were synthesised. Starting from a derivative with an IC(50)=2microM the chemical optimisation program led to compounds with more than a 100-fold increase in potency (IC(50)<20nM). Additionally, physicochemical and pharmacokinetic properties were evaluated. It could be shown that compounds bearing a piperazine or phenyl substituted betaAla-Gly side chain exhibited the best overall profile.