Biological characterization of THRX‐956485, a peripherally‐selective serotonin transport reuptake inhibitor

Peripheral serotonin has been implicated in many therapeutic indications including thrombosis, pulmonary hypertension and osteoporosis. A peripheral selective serotonin reuptake inhibitor (SSRI) without CNS activity could provide a therapeutic index exceeding standard SSRIs. We describe a novel compound that selectively inhibits peripheral serotonin reuptake. THRX‐956485 is a potent (hSERT uptake IC 50 /binding K i = 2.5nM/1.0nM) and selective SERT inhibitor in vitro and is >2500‐ fold selective over other reuptake transporters and serotonin receptors. In rat PK studies (single 5 mg/kg PO), or 14‐day osmotic mini‐pump infusions (0.3, 0.7 and 1.6 mg/kg/day), THRX‐956485 showed pronounced peripheral selectivity compared to a CNS‐penetrant SSRI, fluoxetine. Based on unbound CNS vs. plasma exposures and measured SERT occupancy ex vivo , THRX‐ 956485 was >20‐fold peripherally selective (CSF:unbound plasma concentration ratios varied from 1–5%). Additionally, THRX‐956485 demonstrated a dose‐dependent reduction in blood serotonin concentrations in rats. Following 14‐day infusions, blood serotonin concentrations decreased from 94 ng/mL (vehicle) to 43, 25, and 11 ng/mL at 0.3, 0.7 and 1.6 mg/kg/day, respectively. These findings are consistent with inhibition of platelet serotonin uptake, and suggest that THRX‐956485 is a peripherally selective SSRI.