Local carotid arterial stiffness is an independent determinant of left ventricular remodeling in never-treated hypertensive patients

Purpose: The aim was to investigate the association between blood pressure (BP), carotid stiffness, carotid-femoral pulse wave velocity (cfPWV) and left ventricular (LV) remodeling in never-treated hypertensive patients. Material and methods: 178 never-treated hypertensive underwent transthoracic echocardiography, 24-hour ambulatory BP monitoring (ABPM), local carotid stiffness and regional cfPWV assessed using a high-definition echo-tracking ultrasound system and a tonometric transducer, respectively. LV parameters and arterial stiffness were also considered in dippers and non-dippers. Results: Mean night-time BP best correlated with carotid and LV parameters. Carotid stiffness parameters (β-index, pressure-strain elastic modulus, one-point PWV) correlated with LV mass, relative wall thickness, and E/A ratio while cfPWV correlated only with E/A ratio. In multiple regression analysis, age and mean night-time ABPM had a stroger relation with carotid stiffness than cfPWV. In a second multiple regression analysis, day and night ABPM and carotid stiffness were independently related with LV remodeling and left atrial volume. In non-dippers, local carotid stiffness parameters were significantly higher than in dippers, whereas cfPWV was not significantly different. Conclusions: Carotid stiffness parameters are independently associated with LV remodeling and have an additive effect to BP and over cfPWV moreover local arterial stiffness is higher in non-dippers

Data Summary Report: M-Area Western Sector Remediation Project

This investigation provides stratigraphic and constituent concentration data for the M-Area western sector in situ remedial system location and design

Application of a Parallel Synthetic Strategy in the Discovery of Biaryl Acyl Sulfonamides as Efficient and Selective Na_V1.7 Inhibitors

The majority of potent and selective hNa_V1.7 inhibitors possess common pharmacophoric features that include a heteroaryl sulfonamide headgroup and a lipophilic aromatic tail group. Recently, reports of similar aromatic tail groups in combination with an acyl sulfonamide headgroup have emerged, with the acyl sulfonamide bestowing levels of selectivity over hNa_V1.5 comparable to the heteroaryl sulfonamide. Beginning with commercially available carboxylic acids that met selected pharmacophoric requirements in the lipophilic tail, a parallel synthetic approach was applied to rapidly generate the derived acyl sulfonamides. A biaryl acyl sulfonamide hit from this library was elaborated, optimizing for potency and selectivity with attention to physicochemical properties. The resulting novel leads are potent, ligand and lipophilic efficient, and selective over hNa_V1.5. Representative lead <b>36</b> demonstrates selectivity over other human Na_V isoforms and good pharmacokinetics in rodents. The biaryl acyl sulfonamides reported herein may also offer ADME advantages over known heteroaryl sulfonamide inhibitors

Sulfonamides as Selective Na_V1.7 Inhibitors: Optimizing Potency and Pharmacokinetics While Mitigating Metabolic Liabilities

Several reports have recently emerged regarding the identification of heteroarylsulfonamides as Na_V1.7 inhibitors that demonstrate high levels of selectivity over other Na_V isoforms. The optimization of a series of internal Na_V1.7 leads that address a number of metabolic liabilities including bioactivation, PXR activation, as well as CYP3A4 induction and inhibition led to the identification of potent and selective inhibitors that demonstrated favorable pharmacokinetic profiles and were devoid of the aforementioned liabilities. The key to achieving this within a series prone to transporter-mediated clearance was the identification of a small range of optimal cLogD values and the discovery of subtle PXR SAR that was not lipophilicity dependent. This enabled the identification of compound <b>20</b>, which was advanced into a target engagement pharmacodynamic model where it exhibited robust reversal of histamine-induced scratching bouts in mice

Sulfonamides as Selective Na_V1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity

Because of its strong genetic validation, Na_V1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as Na_V1.7 inhibitors that demonstrate high levels of selectivity over other Na_V isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation. WO 2014201206, 2014] of Na_V1.7, which demonstrate nanomolar inhibition of Na_V1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound <b>39</b> (AM-0466) demonstrated robust pharmacodynamic activity in a Na_V1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity

Sulfonamides as Selective Na_V1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity

Because of its strong genetic validation, Na_V1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as Na_V1.7 inhibitors that demonstrate high levels of selectivity over other Na_V isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation. WO 2014201206, 2014] of Na_V1.7, which demonstrate nanomolar inhibition of Na_V1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound <b>39</b> (AM-0466) demonstrated robust pharmacodynamic activity in a Na_V1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity