Development of a Peripherally Restricted 5-HT2B Partial Agonist for Treatment of Pulmonary Arterial Hypertension

Ligands for the serotonin 2B receptor (5-HT2B) have shown potential to treat pulmonary arterial hypertension in preclinical models but cannot be used in humans because of predicted off-target neurological effects. The aim of this study was to develop novel systemically restricted compounds targeting 5-HT2B. Here, we show that mice treated with VU6047534 had decreased RVSP compared with control treatment in both the prevention and intervention studies using Sugen-hypoxia. VU6047534 is a novel 5-HT2B partial agonist that is peripherally restricted and able to both prevent and treat Sugen-hypoxia–induced pulmonary arterial hypertension. We have synthesized and characterized a structurally novel series of 5-HT2B ligands with high potency and selectivity for the 5-HT2B receptor subtype. Next-generation 5-HT2B ligands with similar characteristics, and predicted to be systemically restricted in humans, are currently advancing to investigational new drug–enabling studies

Surface currents and winds at the Delaware Bay mouth

Knowledge of the circulation of estuaries and adjacent shelf waters has relied on hydrographic measurements, moorings, and local wind observations usually removed from the region of interest. Although these observations are certainly sufficient to identify major characteristics, they lack both spatial resolution and temporal coverage. High resolution synoptic observations are required to identify important coastal processes at smaller scales. Long observation periods are needed to properly sample low-frequency processes that may also be important. The introduction of high-frequency (HF) radar measurements and regional wind models for coastal studies is changing this situation. Here we analyze synoptic, high-resolution surface winds and currents in the Delaware Bay mouth over an eight-month period (October 2007 through May 2008). The surface currents were measured by two high-frequency radars while the surface winds were extracted from a data-assimilating regional wind model. To illustrate the utility of these monitoring tools we focus on two 45-day periods which previously were shown to present contrasting pictures of the circulation. One, the low-outflow period is from 1 October through 14 November 2007; the other is the high-outflow period from 3 March through 16 April 2008. The large-scale characteristics noted by previous workers are clearly corroborated. Specifically the M2 tide dominates the surface currents, and the Delaware Bay outflow plume is clearly evident in the low frequency currents. Several new aspects of the surface circulation were also identified. These include a map of the spatial variability of the M2 tide (validating an earlier model study), persistent low-frequency cross-mouth flow, and a rapid response of the surface currents to a changing wind field. However, strong wind episodes did not persist long enough to set up a sustained Ekman response