Initiation and Up-Titration of Guideline-Based Medications in Hospitalized Acute Heart Failure Patients　- A Report From the West Tokyo Heart Failure Registry.

BACKGROUND: Despite recommendations from clinical practice guidelines to initiate and titrate guideline-directed medical therapy (GDMT) during their hospitalization, patients with acute heart failure (AHF) are frequently undertreated. In this study we aimed to clarify GDMT implementation and titration rates, as well as the long-term outcomes, in hospitalized AHF patients.Methods and Results: Among 3,164 consecutive hospitalized AHF patients included in a Japanese multicenter registry, 1,400 (44.2%) with ejection fraction ≤40% were analyzed. We assessed GDMT dosage (ß-blockers, renin-angiotensin inhibitors, and mineralocorticoid-receptor antagonists) at admission and discharge, examined the contributing factors for up-titration, and evaluated associations between drug initiation/up-titration and 1-year post-discharge all-cause death and rehospitalization for HF via propensity score matching. The mean age of the patients was 71.5 years and 30.7% were female. Overall, 1,051 patients (75.0%) were deemed eligible for GDMT, based on their baseline vital signs, renal function, and electrolyte values. At discharge, only 180 patients (17.1%) received GDMT agents up-titrated to >50% of the maximum titrated dose. Up-titration was associated with a lower risk of 1-year clinical outcomes (adjusted hazard ratio: 0.58, 95% confidence interval: 0.35-0.96). Younger age and higher body mass index were significant predictors of drug up-titration. CONCLUSIONS: Significant evidence-practice gaps in the use and dose of GDMT remain. Considering the associated favorable outcomes, further efforts to improve its implementation seem crucial.

Relationship Between Left Ventricular Ejection Fraction and Treatment Characteristics in Hospitalized Patients With Heart Failure　- A Japanese Database Analysis.

Background: Triple combination therapy with a renin-angiotensin system modulator, a ß-blocker, and a mineralocorticoid receptor antagonist is currently recommended for patients with heart failure (HF) with reduced ejection fraction. However, there is limited evidence on the extent to which triple combination therapy is currently prescribed to patients at the time of discharge from hospital in Japan. Methods and Results: Japanese patients hospitalized for HF (n=3,582) were evaluated in subgroups defined by left ventricular ejection fraction (LVEF) using anonymized claims and electronic health record data. At discharge, triple combination therapy prescription rates were low (40.4%, 30.0%, 20.8%, 14.0%, and 12.5% for patients with LVEF <30%, 30-<40%, 40-<50%, 50-<60%, and ≥60%, respectively). Advanced age, lower levels of B-type natriuretic peptide, and renal impairment were all significantly associated with lower rates of triple combination therapy use in the overall population. There were no significant differences in rehospitalization rates between LVEF subgroups; however, triple combination therapy use was associated with a significantly reduced risk of rehospitalization for HF in patients with LVEF <30%, 30-<40%, and 40-<50%. Conclusions: The use of triple combination therapy was significantly associated with a lower risk of rehospitalization for HF within 1 year of discharge in patients with LVEF <30%, 30-<40%, and 40-<50%. However, patients were undertreated with triple combination therapy.

Discovery of selective and nonpeptidic cathepsin S inhibitors.

Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.

Discovery of a Novel Piperidine-Based Inhibitor of Cholesteryl Ester Transfer Protein (CETP) That Retains Activity in Hypertriglyceridemic Plasma.

Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound 16 (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclinical efficacy and safety profile, the compound was advanced into clinical trials.

Effect of cathepsin K inhibitors on bone resorption.

On the basis of the pyrrolopyrimidine core structure that was previously discovered, cathepsin K inhibitors having a spiro amine at the P3 have been explored to enhance the target, bone marrow, tissue distribution. Several spiro structures were identified with improved distribution toward bone marrow. The representative inhibitor 7 of this series revealed in vivo reduction in C-terminal telopeptide of type I collagen in rats and monkeys.

Novel scaffold for cathepsin K inhibitors.

Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20.

Design and synthesis of 7H-pyrrolo[2,3-d]pyrimidines as focal adhesion kinase inhibitors. Part 2.

A series of 2-amino-9-aryl-7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized as focal adhesion kinase (FAK) inhibitors using molecular modeling in conjunction with a co-crystal structure. Chemistry was developed to introduce functionality onto the 9-aryl ring, which resulted in the identification of potent FAK inhibitors. In particular, compound 32 possessed single-digit nanomolar IC(50) and represents one of the most potent FAK inhibitors discovered to date.