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•Delivery of a potent and selective series of NaV1.7 inhibitors.•Discovery of a novel bioisostere for the acyl sulfonamide.•Diversity-oriented synthesis of triazolesulfones.
Recently, ...the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit NaV1.7 and demonstrate high levels of selectivity over other NaV isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable, selective NaV1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over NaV1.5 and favorable pharmacokinetics in rodents.
The uncertainty on measurements, given by the Heisenberg principle, is a quantum concept usually not taken into account in General Relativity. From a cosmological point of view, several authors ...wonder how such a principle can be reconciled with the Big Bang singularity, but, generally, not whether it may affect the reliability of cosmological measurements. In this letter, we express the Compton mass as a function of the cosmological redshift. The cosmological application of the indetermination principle unveils the differences of the Hubble-Lemaître constant value,
H
0
, as measured from the Cepheids estimates and from the Cosmic Microwave Background radiation constraints. In conclusion, the
H
0
tension could be related to the effect of indetermination derived in comparing a kinematic with a dynamic measurement.
The Heisenberg Limit at Cosmological Scales Spallicci, Alessandro D. A. M.; Benetti, Micol; Capozziello, Salvatore
Foundations of physics,
02/2022, Letnik:
52, Številka:
1
Journal Article
Recenzirano
Odprti dostop
For an observation time equal to the universe age, the Heisenberg principle fixes the value of the smallest measurable mass at
m
H
=
1.35
×
10
-
69
kg and prevents to probe the masslessness for any ...particle using a balance. The corresponding reduced Compton length to
m
H
is
, and represents the length limit beyond which masslessness cannot be proved using a metre ruler. In turns,
is equated to the luminosity distance
d
H
which corresponds to a red shift
z
H
. When using the Concordance-Model parameters, we get
d
H
=
8.4
Gpc and
z
H
=
1.3
. Remarkably,
d
H
falls quite short to the radius of the
observable
universe. According to this result, tensions in cosmological parameters could be nothing else but due to comparing data inside and beyond
z
H
. Finally, in terms of quantum quantities, the expansion constant
H
0
reveals to be one order of magnitude above the smallest measurable energy, divided by the Planck constant.
The observed red shift
z
might be composed by the expansion red shift
z
C
and an additional frequency shift
z
S
, towards the red or the blue, by considering extended theories of electromagnetism ...(ETE). Indeed, massive photon theories—the photon has a real mass as in the de Broglie–Proca theory or an effective mass as in the standard-model extension, based on Lorentz–Poincaré symmetry violation (LSV)—or nonlinear electromagnetism theories may induce a cosmological expansion-independent frequency shift in the presence of background (inter-) galactic electromagnetic fields, and where of relevance LSV fields, even when both fields are constant. We have tested this prediction considering the Pantheon Catalogue, composed by 1048 SNe Ia, and 15 BAO data, for different cosmological models characterised by the absence of a cosmological constant. From the data, we compute which values of
z
S
match the observations, spanning cosmological parameters (
Ω
densities and Hubble–Lemaître constant) domains. We conclude that the frequency shift
z
S
can support an alternative to accelerated expansion, naturally accommodating each SN Ia position in the distance modulus versus red shift diagram, due to the light-path dependency of
z
S
. Finally, we briefly mention laboratory test approaches to investigate the additional shift from ETE predictions.
Progress Toward Cardiac Xenotransplantation Pierson, 3rd, Richard N; Fishman, Jay A; Lewis, Gregory D ...
Circulation (New York, N.Y.),
2020-October-06, Letnik:
142, Številka:
14
Journal Article
Recenzirano
Odprti dostop
Consistent survival of life-supporting pig heart xenograft recipients beyond 90 days was recently reported using genetically modified pigs and a clinically applicable drug treatment regimen. If this ...remarkable achievement proves reproducible, published benchmarks for clinical translation of cardiac xenografts appear to be within reach. Key mechanistic insights are summarized here that informed recent pig design and therapeutic choices, which together appear likely to enable early clinical translation.
Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit Na
1.7 and demonstrate high levels of selectivity over other Na
isoforms have been ...reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable, selective Na
1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over Na
1.5 and favorable pharmacokinetics in rodents.
Aims
Limited therapeutic options are available for the management of atrial fibrillation/flutter (AF/AFL) with concomitant heart failure (HF) with preserved (HFpEF) and mildly reduced ejection ...fraction (HFmrEF). Dronedarone reduces the risk of cardiovascular events in patients with AF, but sparse data are available examining its role in patients with AF complicated by HFpEF and HFmrEF.
Methods and results
ATHENA was an international, multicentre trial that randomized 4628 patients with paroxysmal or persistent AF/AFL and cardiovascular risk factors to dronedarone 400 mg twice daily versus placebo. We evaluated patients with (i) symptomatic HFpEF and HFmrEF (defined as left ventricular ejection fraction LVEF >40%, evidence of structural heart disease, and New York Heart Association class II/III or diuretic use), (ii) HF with reduced ejection fraction (HFrEF) or left ventricular dysfunction (LVEF ≤40%), and (iii) those without HF. We assessed effects of dronedarone versus placebo on death or cardiovascular hospitalization (primary endpoint), other key efficacy endpoints, and safety. Overall, 534 (12%) had HFpEF or HFmrEF, 422 (9%) had HFrEF or left ventricular dysfunction, and 3672 (79%) did not have HF. Patients with HFpEF and HFmrEF had a mean age of 73 ± 9 years, 37% were women, and had a mean LVEF of 57 ± 9%. Over a mean follow‐up of 21 ± 5 months, dronedarone consistently reduced risk of death or cardiovascular hospitalization (hazard ratio 0.76; 95% confidence interval 0.69–0.84) without heterogeneity based on HF status (pinteraction >0.10). This risk reduction in the primary endpoint was consistent across the range of LVEF (as a continuous function) in HF without heterogeneity (pinteraction = 0.71). Rates of death, cardiovascular hospitalization, and HF hospitalization each directionally favoured dronedarone versus placebo in HFpEF and HFmrEF, but these treatment effects were not statistically significant in this subgroup.
Conclusions
Dronedarone is associated with reduced cardiovascular events in patients with paroxysmal or persistent AF/AFL and HF across the spectrum of LVEF, including among those with HFpEF and HFmrEF. These data support a rationale for a future dedicated and powered clinical trial to affirm the net clinical benefit of dronedarone in this population.
Dronedarone for the treatment of atrial fibrillation with concomitant heart failure with preserved and mildly reduced ejection fraction: a post‐hoc analysis of the ATHENA trial.
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