Design of Novel Series of Antimalarial PMX Inhibitors with Increased Half-Life via Molecular Property Optimization.

Plasmepsin X (PMX) has been identified as a multistage antimalarial target. PMX is a malarial aspartyl protease essential for merozoite egress from infected red blood cells and invasion of the host erythrocytes. Previously, we reported the identification of PMX inhibitors by structure-based optimization of a cyclic guanidine core. Preclinical assessment of UCB7362, which displayed both in vitro and in vivo antimalarial activity, revealed a suboptimal dose paradigm (once daily dosing of 50 mg for 7 days for treatment of uncomplicated malaria) relative to current standard of care (three-dose regime). We report here the efforts toward extending the half-life (t1/2) by reducing metabolic clearance and increasing volume of distribution (Vss). Our efforts culminated in the identification of a biaryl series, with an expected longer t1/2 in human than UCB7362 while maintaining a similar in vitro off-target hit rate.

Late-Stage 18 F-Difluoromethyl Labeling of N-Heteroaromatics with High Molar Activity for PET Imaging.

Despite a growing interest in CHF2 in medicinal chemistry, there is a lack of efficient methods for the insertion of CHF18 F into druglike compounds. Herein described is a photoredox flow reaction for 18 F-difluoromethylation of N-heteroaromatics that are widely used in medicinal chemistry. Following the two-step synthesis for a new 18 F-difluoromethylation reagent, the photoredox reaction is completed within two minutes and proceeds by C-H activation, circumventing the need for pre-functionalization of the substrate. The method is operationally simple and affords straightforward access to radiolabeled N-heteroaromatics with high molar activity suitable for biological in vivo studies and clinical application.

Direct sulfonylation of anilines mediated by visible light.

Sulfones feature prominently in biologically active molecules and are key functional groups for organic synthesis. We report a mild, photoredox-catalyzed reaction for sulfonylation of aniline derivatives with sulfinate salts, and demonstrate the utility of the method by the late-stage functionalization of drugs. Key features of the method are the straightforward generation of sulfonyl radicals from bench-stable sulfinate salts and the use of simple aniline derivatives as convenient readily available coupling partners.

5-HT7 Receptor Antagonists with an Unprecedented Selectivity Profile.

Selective leads: In this study, we generated a new series of serotonin 5-HT7 receptor antagonists. Their synthesis, structure-activity relationships, and selectivity profiles are reported. This series includes 5-HT7 antagonists with unprecedented high selectivity for the 5-HT7 receptor, setting the stage for lead optimization of drugs acting on a range of neurological targets.

C-H Cyanation of 6-Ring N-Containing Heteroaromatics.

Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far-reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C-H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one-pot protocol is simple to perform, is applicable to a broad range of decorated 6-ring N-containing heterocycles, and has been shown to be suitable for late-stage functionalization of complex drug-like architectures.

Outcomes after ablation for typical atrial flutter (from the Loire Valley Atrial Fibrillation Project).

Similar predisposing factors are found in most types of atrial arrhythmias. The incidence of atrial fibrillation (AF) among patients with atrial flutter is high, suggesting similar outcomes in patients with those arrhythmias. We sought to investigate the long-term outcomes and prognostic factors of patients with AF and/or atrial flutter with contemporary management using radiofrequency ablation. In an academic institution, we retrospectively examined the clinical course of 8,962 consecutive patients admitted to our department with a diagnosis of AF and/or atrial flutter. After a median follow-up of 934 ± 1,134 days, 1,155 deaths and 715 stroke and/thromboembolic (TE) events were recorded. Patients with atrial flutter undergoing cavotricuspid isthmus ablation (n = 875, 37% with a history of AF) had a better survival rate than other patients (hazard ratio [HR] 0.35, 95% confidence interval [CI] 0.25 to 0.49, p <0.0001). Using Cox proportional hazards model and propensity score model, after adjustment for main other confounders, ablation for atrial flutter was significantly associated with a lower risk of all-cause mortality (HR 0.55, 95% CI 0.36 to 0.84, p = 0.006) and stroke and/or TE events (HR 0.53, 95% CI 0.30 to 0.92, p = 0.02). After ablation, there was no significant difference in the risk of TE between patients with a history of AF and those with atrial flutter alone (HR 0.83, 95% CI 0.41 to 1.67, p = 0.59). In conclusion, in patients with atrial tachyarrhythmias, those with atrial flutter with contemporary management who undergo cavotricuspid isthmus radiofrequency ablation independently have a lower risk of stroke and/or TE events and death of any cause, whether a history of AF is present or not.

Programming implantable cardioverter-defibrillators in primary prevention: higher or later.

Defibrillator shocks, appropriate or not, are associated with significant morbidity, as they decrease quality of life, can be involved in depression and anxiety, and are known to be proarrhythmic. Most recent data have even shown an association between shocks and overall mortality. As opposed to other defibrillator-related complications, the rate of inappropriate and unnecessary shocks can (and should) be decreased with adequate programming. This review focuses on the different programming strategies and tips available to reduce the rate of shocks in primary prevention patients with left ventricular dysfunction implanted with a defibrillator, as well as some of the manufacturers' device specificities.

Prognosis in patients hospitalized with permanent and nonpermanent atrial fibrillation in heart failure.

Atrial fibrillation (AF) and heart failure (HF) frequently coexist and are associated with an increased mortality. This study evaluated the prognosis of permanent and nonpermanent AF in patients with both AF and HF. All AF patients seen in our institution were identified and followed up. We included 1,906 patients suffering from AF and HF: 839 patients (44%) had preserved left ventricular ejection fraction (LVEF) and 1,067 patients (56%) had decreased LVEF; 1,056 patients (55%) had nonpermanent AF and 850 patients (45%) had permanent AF. During a median follow-up of 1.9 years (interquartile range 0.3 to 5.0), 377 patients died, 462 were readmitted for HF, and 200 had stroke or thromboembolic events. In patients with decreased LVEF, the rate of death was similar in patients with permanent or nonpermanent AF. In patients with preserved LVEF, permanent AF was associated with a higher risk of death and a higher risk of HF hospitalization. Stroke risk did not differ with permanent AF whatever the LVEF. NYHA functional class was an independent predictor of death (risk ratio [RR]=1.33, 95% confidence interval [CI] 1.12 to 1.59, p=0.001), as was permanent AF (RR=1.79, 95%CI 1.32 to 2.42, p=0.0002). Permanent AF (RR=1.52, 95% CI 1.20 to 1.93, p=0.0006) was also an independent predictor of readmission for HF. In conclusion, in patients with AF and HF, the risk of admission for HF and risk of death were higher when AF was permanent, particularly in patients with preserved LVEF. Stroke risk did not differ according to the pattern of AF, whatever the LVEF.

Discovery of heterocyclic nonacetamide synaptic vesicle protein 2A (SV2A) ligands with single-digit nanomolar potency: opening avenues towards the first SV2A positron emission tomography (PET) ligands.

The role of the synaptic vesicle protein 2A (SV2A) protein, target of the antiepileptic drug levetiracetam, is still mostly unknown. Considering its potential to provide in vivo functional insights into the role of SV2A in epileptic patients, the development of an SV2A positron emission tomography (PET) tracer has been undertaken. Using a 3D pharmacophore model based on close analogues of levetiracetam, we report the rationale design of three heterocyclic non-acetamide lead compounds, UCB-A, UCB-H and UCB-J, the first single-digit nanomolar SV2A ligands with suitable properties for development as PET tracers.

Pattern of atrial fibrillation and risk of outcomes: the Loire Valley Atrial Fibrillation Project.

BACKGROUND: Risk of stroke and thromboembolism (TE) in patients with non-valvular atrial fibrillation (NVAF) is categorised in stroke risk stratification scores. The role of pattern of NVAF in risk prediction is unclear in contemporary 'real world' cohorts. METHODS AND RESULTS: Patients with NVAF in a four-hospital-institution between 2000 and 2010 were included. Stroke/TE event rates were calculated according to pattern of AF, i.e. paroxysmal, persistent and permanent. Risk factors were investigated by Cox regression. Among 7156 NVAF patients, 4176 (58.4%) patients with paroxysmal, 376 (5.3%) with persistent and 2604 (36.3%) with permanent patterns of NVAF were included. In non-anticoagulated patients, overall stroke/TE event rate per 100 person-years was 1.29 (95% CI 1.13-1.47). Compared with paroxysmal NVAF, rates of stroke/TE, bleeding and all-cause mortality (p<0.001) were significantly higher in permanent NVAF patients but not in persistent NVAF patients. In multivariate analyses, previous stroke (hazard ratio, HR 2.58, 95% CI 2.08-3.21), vascular disease (HR 1.34, 1.12-1.61), heart failure (HR 1.20, 1.00-1.44), age ≥ 75 years (HR 2.75, 2.16-3.50) and age 65-74 years (HR 1.60, 1.22-2.09) independently increased stroke/TE risk, but not persistent (HR 1.13, 0.76-1.70) and permanent (HR 1.44, 0.96-2.16) NVAF patterns. CONCLUSION: In this large 'real world' NVAF cohort, rates of stroke, TE, death and bleeding differed significantly by patterns of NVAF. However, only previous stroke, age, heart failure and vascular disease (not pattern of NVAF) independently increased risk of adverse outcomes in multivariate analyses. Thus, stroke risk is similar across all patterns of NVAF and antithrombotic therapy should be based on clinical risk factors, not on arrhythmia pattern.

Long-term follow-up on high-rate cut-off programming for implantable cardioverter defibrillators in primary prevention patients with left ventricular systolic dysfunction.

AIMS: Implantable cardioverter defibrillators (ICDs) are efficient in reducing mortality in patients with left ventricular systolic dysfunction. High-rate cut-off programming may be effective in reducing appropriate and inappropriate therapies, but as the long-term consequences on morbidity and mortality remain unclear, it is underutilized. METHODS AND RESULTS: We prospectively studied 365 consecutive patients (mean age 60 ± 10 years), with ischaemic (63%) or non-ischaemic cardiomyopathy and left ventricular dysfunction (mean ejection fraction 25 ± 7%), who were implanted with an ICD in primary prevention of sudden cardiac death (41% single chamber, 31% dual chamber, and 28% biventricular). All devices were programmed with a shock-only zone over 220 beats per minute (b.p.m.) and a monitoring zone between 170 and 220 b.p.m. During a median follow-up of 40 months, 41 patients received appropriate shocks (11.2%) and 24 inappropriate shocks (6.6%). Then, 306 patients never experienced any ICD shock (84%). Inappropriate discharges were related to supraventricular tachyarrhythmia in 10 patients, and noise/oversensing in 14 patients. Ventricular tachycardia episodes, sustained or not, were recorded in the monitoring zone in 43 patients (11.8%). Seven of these patients were symptomatic (1.9%), without lethal consequence. Sixty-two patients (17%) died: 35 from end-stage heart failure, 1 from unexplained sudden death, and 26 from a documented non-cardiac cause. CONCLUSION: High-rate cut-off (220 b.p.m.) shock-only ICD programming, in primary prevention patients with reduced left ventricular ejection fraction, appeared to be safe during a long-term follow-up. It also resulted in a very low rate of discharges, which are known to be deleterious in this population.

Ejection fraction and outcomes in patients with atrial fibrillation and heart failure: the Loire Valley Atrial Fibrillation Project.

AIMS: Heart failure (HF) increases the risk of stroke and thrombo-embolism (TE) in non-valvular atrial fibrillation (NVAF), and is incorporated in stroke risk stratification scores. We aimed to establish the role of ejection fraction (EF) in risk prediction in patients with NVAF and HF. METHODS AND RESULTS: Patients with NVAF, history of HF, and measured EF were included in a retrospective analysis. Patients with HF and preserved ejection fraction (HFPEF) were defined as those with clinical HF and EF ≥50% in this study. Among 7156 patients with NVAF, 1276 (17.8%) patients with HF and measured EF were included. Of these, 747/1276 (58.5%) patients were on vitamin K antagonists. The stroke/TE event rate per 100 person-years was 1.05 [95% confidence interval (CI) 0.87-1.25]. Patients with HFPEF were more likely to be female (P < 0.001), older (P < 0.001), and hypertensive (P < 0.001), and less likely to have prior vascular disease (P < 0.001). There were no differences in rates of stroke (P = 0.17) and stroke/TE (P = 0.11) between patients with HFPEF and those with HF and reduced EF. There were no significant differences in rates of all-cause mortality when patients were stratified by EF. In multivariate analyses, only previous stroke (hazard ratio 2.36, 95% CI 1.45-3.86) and vascular disease (1.57, 1.07-2.30) increased the risk of stroke/TE amongst NVAF patients with HF, but EF <35% did not (0.75, 0.44-1.30). CONCLUSION: In NVAF patients with HF, there were no differences in rates of stroke, TE, or death between EF categories. Only previous stroke and vascular disease (and not decreased EF) independently increased risk of stroke/TE in multivariate analyses.

Left retropectoral axillary implantation of defibrillators in young women.

We propose a complete surgical approach by left retropectoral transaxillary implantation with no vein puncture to improve the aesthetic and psychological tolerance of the implantable cardioverter defibrillator and avoid the pneumothorax and the subclavian crush syndrome.

The evolution of infrahissian conduction time in myotonic dystrophy patients: clinical implications.

BACKGROUND: Myotonic dystrophy (MD1) is a hereditary autosomal dominant disease with variable penetrance. Cardiac conduction disturbances are frequent and may be responsible for sudden death, but its progression was heretofore unknown. AIMS: The aim of the study was to analyse the natural history of infrahissian conduction time in patients with a normal first electrophysiological test, and to identify the predictive value of the clinical and ECG factors accompanying an alteration of infrahissian conduction. METHODS: Among 127 consecutive screened MD patients, 25 were enrolled and underwent a second electrophysiological testing. The second electrophysiological test was carried out on patients showing new symptoms, new atrioventricular conduction disturbances on ECG, or significant modifications of signal-averaged (SA)-ECG, and on asymptomatic patients with a follow-up of at least 60 months since the first electrophysiological test. RESULTS: Among the 25 patients, four had new clinical symptoms, four others developed new atrioventricular conduction abnormalities on ECG and six had significant modifications of the SA-ECG. The mean His-ventricle (HV) interval increased significantly between the two electrophysiological studies (initial HV interval 52.1 ms±1.6 ms, final HV interval 61.4 ms±2.2 ms, p<0.005), with a mean increase of 1.2 ms/year. The five patients with HV interval of 70 ms or greater were implanted with a prophylactic dual-chamber pacemaker. Modifications of resting ECG and SA-ECG were strongly associated with HV interval prolongation. CONCLUSION: In patients with a normal initial electrophysiological study, modifications on the resting ECG and/or SA-ECG, on annual check-up, were associated with an alteration of infrahissian conduction.

[When do you implant a pacemaker in myotonic dystrophy?]. / Quand implanter un stimulateur cardiaque dans la maladie de Steinert?

Myotonic dystrophy is the most frequent adult form of hereditary muscular dystrophy caused by a mutation on the DMPK gene. Myotonic dystrophy leads to multiple systemic complications related to weakness, respiratory failure, cardiac arrhythmias and cardiac conduction disturbances. Age of death is earlier in myotonic dystrophy patients than in general population with a high frequency of sudden death. Several mechanisms are involved in sudden death: atrio-ventricular block, severe ventricular arrhythmias or non-cardiac mechanism. The high degree of atrio-ventricular block is a well-recognized indication of pacemaker implantation but the prophylactic implantation of pacemaker should be considered to prevent sudden death in asymptomatic myotonic dystrophy patients. A careful clinical evaluation needs to be done for the identification of patients at high risk of sudden death. The resting ECG and SA ECG are non-invasive tools useful to select the patients who need an electrophysiologic study. In presence of prolonged HV interval more than or equal to 70 ms one can discuss the implantation of a prophylactic pacemaker. The choice of an implantable cardiac defibrillator is preferred in presence of spontaneous ventricular tachycardia or an alteration of the left ventricular ejection fraction.

Discovery of a new class of non-imidazole oxazoline-based histamine H(3) receptor (H(3)R) inverse agonists.

H(3)R inverse agonists based on an aminopropoxy-phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.

Discovery of 4-azaindoles as novel inhibitors of c-Met kinase.

A series of 4-azaindole inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and series optimisation was performed on the basis of this structure. Future directions for series development are discussed.

4-benzyl-1H-imidazoles with oxazoline termini as histamine H3 receptor agonists.

Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research.