Dataset Information

First-in-human study with ACT-539313, a novel selective orexin-1 receptor antagonist.

ABSTRACT: AIMS:The orexin system is involved in anxiety behaviour and corresponding physiological reactions and constitutes a target for treatment of anxiety disorders. ACT-539313 is a potent, selective orexin-1 receptor antagonist being developed for the treatment of anxiety disorders. This first-in-human study investigated its single-dose pharmacokinetics (PK) including food effect, pharmacodynamics (PD), safety and tolerability. METHODS:This double-blind, placebo-controlled, randomized study included 40 healthy male subjects. Ascending oral doses of 10-400 mg ACT-539313 were investigated in 5 dose groups of 8 subjects (of whom 2 received placebo per dose group). At 100 mg, subjects received ACT-539313 in fasted and fed conditions in a fixed sequential design. PK, PD (objective and subjective measures of sedation and effects on central nervous system), safety and tolerability were assessed. RESULTS:In fasted conditions, ACT-539313 was rapidly absorbed (median time to maximum plasma concentration [Cmax ] 0.7-3.5 h) and cleared from plasma with a mean terminal half-life of 3.3-5.7 h across dose levels. A 1.63-fold (90% confidence interval: 1.26-2.11) increase in Cmax and no change in area under the concentration-time curve extrapolated to infinity was observed under fed compared to fasted conditions. No relevant PD signals were detected except for a trend of reduced saccadic peak velocity around time to Cmax . The most commonly reported adverse events were somnolence and headache. All adverse events were transient and of mild or moderate intensity. No treatment-related effects on vital signs, clinical laboratory or 12-lead electrocardiogram were observed. CONCLUSIONS:ACT-539313 exhibits good safety and tolerability at single doses of up to and including 400 mg that warrant further investigations.

SUBMITTER: Kaufmann P

PROVIDER: S-EPMC7319015 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:The orexin system regulates feeding, nutrient metabolism and energy homeostasis. Acute pharmacological blockade of orexin receptor 1 (OXR-1) in rodents induces satiety and reduces normal and palatable food intake. Genetic OXR-1 deletion in mice improves hyperglycemia under high-fat (HF) diet conditions. Here we investigated the effects of chronic treatment with the novel selective OXR-1 antagonist ACT-335827 in a rat model of diet-induced obesity (DIO) associated with metabolic syndrome (MetS). Rats were fed either standard chow (SC) or a cafeteria (CAF) diet comprised of intermittent human snacks and a constant free choice between a HF/sweet (HF/S) diet and SC for 13 weeks. Thereafter the SC group was treated with vehicle (for 4 weeks) and the CAF group was divided into a vehicle and an ACT-335827 treatment group. Energy and water intake, food preference, and indicators of MetS (abdominal obesity, glucose homeostasis, plasma lipids, and blood pressure) were monitored. Hippocampus-dependent memory, which can be impaired by DIO, was assessed. CAF diet fed rats treated with ACT-335827 consumed less of the HF/S diet and more of the SC, but did not change their snack or total kcal intake compared to vehicle-treated rats. ACT-335827 increased water intake and the high-density lipoprotein associated cholesterol proportion of total circulating cholesterol. ACT-335827 slightly increased body weight gain (4% vs. controls) and feed efficiency in the absence of hyperphagia. These effects were not associated with significant changes in the elevated fasting glucose and triglyceride (TG) plasma levels, glucose intolerance, elevated blood pressure, and adiposity due to CAF diet consumption. Neither CAF diet consumption alone nor ACT-335827 affected memory. In conclusion, the main metabolic characteristics associated with DIO and MetS in rats remained unaffected by chronic ACT-335827 treatment, suggesting that pharmacological OXR-1 blockade has minimal impact in this model.

Project description:1. This study characterises the binding of a novel nonpeptide antagonist radioligand, [(3)H]SB-674042 (1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone), to the human orexin-1 (OX(1)) receptor stably expressed in Chinese hamster ovary (CHO) cells in both a whole cell assay and in a cell membrane-based scintillation proximity assay (SPA) format. 2. Specific binding of [(3)H]SB-674042 was saturable in both whole cell and membrane formats. Analyses suggested a single high-affinity site, with K(d) values of 3.76+/-0.45 and 5.03+/-0.31 nm, and corresponding B(max) values of 30.8+/-1.8 and 34.4+/-2.0 pmol mg protein(-1), in whole cell and membrane formats, respectively. Kinetic studies yielded similar K(d) values. 3. Competition studies in whole cells revealed that the native orexin peptides display a low affinity for the OX(1) receptor, with orexin-A displaying a approximately five-fold higher affinity than orexin-B (K(i) values of 318+/-158 and 1516+/-597 nm, respectively). 4. SB-334867, SB-408124 (1-(6,8-difluoro-2-methyl-quinolin-4-yl)-3-(4-dimethylamino-phenyl)-urea) and SB-410220 (1-(5,8-difluoro-quinolin-4-yl)-3-(4-dimethylamino-phenyl)-urea) all displayed high affinity for the OX(1) receptor in both whole cell (K(i) values 99+/-18, 57+/-8.3 and 19+/-4.5 nm, respectively) and membrane (K(i) values 38+/-3.6, 27+/-4.1 and 4.5+/-0.2 nm, respectively) formats. 5. Calcium mobilisation studies showed that SB-334867, SB-408124 and SB-410220 are all functional antagonists of the OX(1) receptor, with potencies in line with their affinities, as measured in the radioligand binding assays, and with approximately 50-fold selectivity over the orexin-2 receptor. 6. These studies indicate that [(3)H]SB-674042 is a specific, high-affinity radioligand for the OX(1) receptor. The availability of this radioligand will be a valuable tool with which to investigate the physiological functions of OX(1) receptors.

Dataset Information

First-in-human study with ACT-539313, a novel selective orexin-1 receptor antagonist.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets