Synthesis and pharmacological evaluation of N-{4-[2-(4-arylpiperazin-1-yl) ethyl] phenyl}arylamides

Serotonin 5HT1a receptor belongs to a class of G-protein coupled receptors. It serves as a potential target for neurological disorders such as depression, anxiety etc. It is a well-known fact that N-arylpiperazine moiety is present in compounds with pronounced 5HT1a activity. Taking into account previously published results1 novel structures of N-{4-[2-(4- arylpiperazin-1-yl)ethyl]phenyl}arylamides (Figure 1.) were designed for target synthesis. Proposed modifications include: different position of hydroxyl group in aryl amide part of molecule and addition of methoxy and chloro substituents to the phenyl ring of parent compounds, since their introduction in the molecule leads to increased receptor affinity. New compounds were synthesized by acylation of N-arylpiperazines using 4- nitrophenylacetic acid. Obtained amides were converted in 1-(4-nitrophenethyl)-4- arylpiperazines using diborane in THF. Reduction of nitro compounds by Ra/Ni provided 1- (4-aminophenethyl)-4-arylpiperazines. Target arylamides were obtained by condensation 1- (4-aminophenethyl)-4-arylpiperazines with corresponding aryl acids in presence of propylphosphoric acid anhydride (PPAA) in DMF. All newly synthesized compounds were evaluated for their activity toward 5HT1a receptors by in vitro competitive displacement assay of [3H] 8-OH-DPAT. HEK cell line were used as a source of 5HT1a receptors. Introduction of 2-methoxy and 2,3-dichloro groups,as well as meta and para hydroxyl group in molecule resulted in increment of affinity toward 5HT1a receptors comparing to the parent compounds

Development of fluorinated indanone-based derivatives for the imaging of monoamine oxidase B via positron emission tomography

Ziel/Aim The monoamine oxidase B (MAO B) isoenzyme is known to be involved in the oxidative deamination of biogenic amines. While the use of MAO B inhibitors is already well-established for the treatment of Parkinson’s disease, recent reports suggest its involvement in certain types of brain tumors.1 We herein aim at the synthesis and preclinical evaluation of fluorinated indanone-based derivatives targeting MAO B in the brain via positron emission tomography (PET). Methodik/Methods A small series of fluorinated indanone derivatives was obtained via the O-alkylation or esterification starting with the commercially available 6-hydroxy-2,3-dihydro-1H-inden-1-one in one or two steps. Binding affinities towards the human MAO isoenzymes were estimated in vitro by radioligand displacement. HL126 was selected for radiofluorination via its corresponding boronic acid pinacol ester. In vitro autoradiography of [18F]HL126 was performed in mice brain slices. In vivo evaluation of [18F]HL126 in CD-1 mice was carried out and metabolism studies were performed in plasma and brain samples via radio-HPLC. Ergebnisse/Results The fluorinated indanone derivatives were synthesized in yields ranging from 65-89 %. The fluorophenyl ether derivative, HL126, was further selected for radiofluorination based on its high binding affinity towards MAO B (Ki = 6.9 ± 5.3 nM). [18F]HL126 was obtained by an alcohol-enhanced copper-mediated approach via the corresponding boronic acid pinacol ester precursor with radiochemical yields of about 11 ± 3 %, high radiochemical purities (≥99 %) and molar activities in the range of 20 GBq/mmol. In vitro autoradiography showed a specific blockade with selective MAO-A/B inhibitors. PET/MRI analyses revealed that [18F]HL126 readily enters the brain. Some radiometabolites do cross the blood-brain barrier. Schlussfolgerungen/Conclusions Although metabolism studies with [18F] HL126 revealed the presence of radiometabolites in the brain, the high binding affinity towards MAO B and the pronounced selectivity in in vitro autoradiography studies encourage further derivatization of indanone-based scaffolds for targeting MAO B

Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Searches for Neutrinos from Gamma-Ray Bursts using the IceCube Neutrino Observatory

Gamma-ray bursts (GRBs) are considered as promising sources of ultra-high-energy cosmic rays (UHECRs) due to their large power output. Observing a neutrino flux from GRBs would offer evidence that GRBs are hadronic accelerators of UHECRs. Previous IceCube analyses, which primarily focused on neutrinos arriving in temporal coincidence with the prompt gamma rays, found no significant neutrino excess. The four analyses presented in this paper extend the region of interest to 14 days before and after the prompt phase, including generic extended time windows and targeted precursor searches. GRBs were selected between May 2011 and October 2018 to align with the data set of candidate muon-neutrino events observed by IceCube. No evidence of correlation between neutrino events and GRBs was found in these analyses. Limits are set to constrain the contribution of the cosmic GRB population to the diffuse astrophysical neutrino flux observed by IceCube. Prompt neutrino emission from GRBs is limited to $\lesssim$1% of the observed diffuse neutrino flux, and emission on timescales up to $10^4$ s is constrained to 24% of the total diffuse flux

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years