bay-94-8862 and Chronic-Disease

There have been few major breakthroughs in heart failure (HF) drug therapies in recent years yet HF morbidity and mortality remain high, and there is a clear need for further research. Several newer agents that appear promising in Phase I and II trials do not progress to show clinical benefit in later trials. Part of the failure to find new therapies may lie in flawed trial design compounded by the need for ever-increasing patient numbers in order to prove outcome benefit. We summarize some of the most recent and promising medical therapies for HF.

Topics: Amides; Cardiotonic Agents; Chronic Disease; Diuretics; Forecasting; Fumarates; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Myocardial Contraction; Naphthyridines; Oligopeptides; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Vasodilator Agents

Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, was evaluated in Japanese patients with heart failure (HF) with reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.. ARTS-HF Japan was a randomized, double-blind, phase 2b study. Patients (n=72) received oral, once-daily (o.d.) finerenone (2.5, 5, 7.5, 10 or 15 mg, up-titrated to 5, 10, 15, 20, or 20 mg, respectively, on day 30) or eplerenone (25 mg every other day, increased to 25 mg o.d. on day 30, and 50 mg on day 60) for 90 days. The primary endpoint was the proportion of individuals with a decrease of >30% in plasma NT-proBNP at day 90. Safety endpoints included the incidence of hyperkalemia. Decreases in NT-proBNP occurred in 23.1% of patients in the eplerenone group and 15.4%, 23.1%, 45.5%, 27.3% and 45.5% in the 2.5→5 mg, 5→10 mg, 7.5→15 mg, 10→20 mg and 15→20 mg finerenone groups, respectively (all P=NS). Mean changes in serum potassium levels were similar between groups.. Because of the small sample size, limited conclusions can be drawn. Considering the results of ARTS-HF and that finerenone was well tolerated in Japanese patients in ARTS-HF Japan, the safety and efficacy of finerenone should be further explored in a large outcomes trial including Japanese patients. (Circ J 2016; 80: 1113-1122).

Topics: Adult; Chronic Disease; Diabetes Mellitus; Double-Blind Method; Eplerenone; Heart Failure; Humans; Hyperkalemia; Japan; Naphthyridines; Natriuretic Peptide, Brain; Patient Safety; Peptide Fragments; Renal Insufficiency, Chronic; Spironolactone

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.

Topics: Animals; Binding Sites; Chronic Disease; Computer Simulation; Drug Evaluation, Preclinical; Heart Failure; Humans; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Naphthyridines; Potassium; Protein Structure, Tertiary; Rats; Receptors, Mineralocorticoid; Sodium