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.

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.

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.

No abstract

No abstract

The pharmacokinetics of BAY 59-7939 - a novel, oral, direct Factor Xa inhibitor - were investigated in rats and dogs in support of preclinical safety studies and clinical development. BAY 59-7939 was rapidly absorbed after oral dosing, with an absolute bioavailability of 57-66% in rats, and 60-86% in dogs. Plasma pharmacokinetics of BAY 59-7939 were linear across the investigated dose range (1-10 mg kg(-1) in rats, 0.3-3 mg kg(-1) in dogs). Plasma clearance was low: 0.4 l kg(-1) h(-1) in rats and 0.3 l kg(-1) h(-1) in dogs; volume of distribution (V(ss)) was moderate: 0.3 l kg(-1) in rats, and 0.4 l kg(-1) in dogs. The elimination half-life after oral administration was short in both species (0.9-2.3 h). Whole-body autoradiography showed moderate tissue affinity. No retention or small volume enrichments of BAY 59-7939-related radioactivity were observed. The plasma-protein binding of BAY 59-7939 was high, species dependent and fully reversible. BAY 59-7939 was rapidly excreted in rats and dogs, and was not irreversibly retained. A dual mode of excretion (biliary/faecal and renal) was observed. In summary, BAY 59-7939 had a favourable, predictable pharmacokinetic profile, with high oral bioavailability and a dual route of excretion.

Direct stimulation of soluble guanylate cyclase (sGC) represents a promising therapeutic strategy for the treatment of a range of diseases, including the severely disabling pulmonary hypertension (PH). Optimization of the unfavorable DMPK profile of previous sGC stimulators provided riociguat, which is currently being investigated in phase III clinical trials for the oral treatment of PH.magnified imageSoluble 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.

No abstract