Pharmacokinetics, Safety, and Tolerability of the α_2C‐Adrenoreceptor Antagonist BAY 1193397 in Healthy Male Subjects

Abstract

The α 2C -adrenoreceptor antagonist BAY 1193397 is in development for the oral treatment of diabetic foot ulcers. Safety, tolerability, and pharmacokinetics of BAY 1193397 were investigated in 3 randomized, single-center phase 1 studies in healthy male subjects: a first-in-human study (single oral doses of 0.5-50 mg), a relative bioavailability and food effect study (single doses of 1 and 10 mg), and a multiple-dose escalation study (using 2 and 5 mg twice daily and 10 and 20 mg once daily for 9 consecutive days). BAY 1193397 was rapidly absorbed in the fasted state, peak concentrations were reached between 0.6 and 2 hours. The mean terminal half-life was in the range of 17 to 20 hours. Area under the plasma concentration-time curve and maximum concentration appeared to be dose proportional, with a negligible food effect. There were no high-accumulation effects of BAY 1193397 after repeated dosing. BAY 1193397 was safe and well tolerated. At supratherapeutic plasma concentrations, there were slight transient increases in norepinephrine levels, heart rate, and blood pressure that were more pronounced after a single dose compared to steady state and appeared to be maximum concentration dependent. The results of the presented studies support the conduct of subsequent clinical trials with BAY 1193397 in patients with diabetes and compromised microcirculation.

Inhibiting Intracellular α2C-Adrenoceptor Surface Translocation Using Decoy Peptides: Identification of an Essential Role of the C-Terminus in Receptor Trafficking

“…Particularly, interest in inhibiting the biological activity of vascular α 2C -adrenoceptors (which play a role as thermo-effectors) has grown over the years and includes the recent elucidation of crystal structure to identify molecular interactions during ligand binding which can aid in designing selective α 2C -adrenoceptor antagonists [35]. Indeed, clinical trials have been performed using α 2C -adrenoceptor antagonists targeting cell surface receptors and include compounds OPC-28326, ORM-12471, and BAY1193397 [36,37]. However, since this receptor is also expressed on the cell surface in non-VSM cells, other tissues, and organs, this approach, although promising in short-term trials, also showed an effect on inhibiting pre-synaptic α 2C -adrenoceptors and in augmenting sympathetic activity over long-term use, which affects heart function [38].…”