TAS-303, a Novel Selective Norepinephrine Reuptake Inhibitor that Increases Urethral Pressure in Rats, Indicating Its Potential as a Therapeutic Agent for Stress Urinary Incontinence

Abstract

Stress urinary incontinence (SUI) is characterized by involuntary leakage associated with exertion, effort, sneezing, coughing, or lifting. Duloxetine, a serotonin norepinephrine reuptake inhibitor, is approved for the treatment of patients with SUI in some European countries, but not in the United States. There is currently no globally approved pharmacological drug for the treatment of patients with SUI. Therefore, a new pharmacological treatment option is required. TAS-303 [4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3- )acetate hydrochloride] is a novel small-molecule selective norepinephrine reuptake inhibitor that displays significant norepinephrine transporter (NET) inhibitory activity toward the serotonin or dopamine transporters. In this report, we describe the pharmacological properties of TAS-303 and its effects on urethral function, using preclinical in vitro and in vivo studies. Radioligand-binding studies showed that TAS-303 selectively and potently inhibited [H]norepinephrine binding to the human NET. Oral administration of TAS-303 (3 mg/kg) significantly increased norepinephrine levels in the plasma, whereas it did not significantly affect epinephrine, dopamine, and serotonin levels. TAS-303 (0.3, 1, and 3 mg/kg) dose-dependently increased basal urethral pressure in normal rats and leak point pressure in vaginal distention rats, exhibiting a maximal effect comparable to duloxetine. In the forced swimming test, TAS-303 (100 mg/kg) showed no significant effects on immobility time in rats, raising the possibility that this agent would have minimal central nervous system side effects at an effective dose for urethral function. These results demonstrate that TAS-303 has therapeutic potential for the treatment of patients with SUI.

A Drug‐Drug Interaction Study to Evaluate the Effect of TAS‐303 on CYP3A Activity in the Small Intestine and Liver

“…This condition considerably compromises the quality of life for many women . TAS‐303 (4‐piperidinyl 2,2‐diphenyl‐2‐ [propoxy‐1,1,2,2,3,3,3‐ d 7 ] acetate hydrochloride; Supplemental Figure S1) is a selective noradrenaline reuptake inhibitor that is being investigated as a novel therapy for SUI . In nonclinical studies, TAS‐303 had a time‐dependent inhibitory effect on cytochrome P450 (CYP) 3A, half‐maximal inactivation (K I , 1024 ng/mL), and a maximal inactivation rate constant (K inact , 4.68 h −1 ); unpublished data.…”

TAS-303 Ameliorates Carbachol-Induced Detrusor Overactivity in Rats, Revealing Its Therapeutic Potential for Overactive Bladder

“…These reports suggest that M3 receptors and β3 adrenoreceptors coordinately regulate the bladder afferents. We previously reported that the concentration of norepinephrine in plasma after TAS-303 administration is elevated in rats (Mizutani et al, 2018). Thus, we hypothesized that norepinephrine elevation due to inhibition of the norepinephrine transporter (NET) may contribute to suppression of bladder afferents via β3 adrenoreceptors.…”

“…TAS-303 hydrochloride was synthesized by Taiho Pharmaceutical Co. Ltd. The chemical structure and pharmacological properties of TAS-303 were previously described (Mizutani et al, 2018). Atropine sulfate salt monohydrate, carbamoylcholine chloride (carbachol), and nisoxetine hydrochloride were purchased from Sigma-Aldrich Japan K.K.…”

“…The micturition volume and bladder capacity, but not micturition pressure, improved after administration of TAS-303 in a dose-dependent manner compared with the vehicle group (Supplemental Figure 1). JPET # 264572 inhibition of M3 receptors (1.13 μM) (Table 2; Mizutani et al, 2018). Therefore, a mechanism of action in addition to inhibition of M3 receptors was considered to underlie the increase in the inter-contraction interval after administration of TAS-303.…”

“…TAS-303, which is a selective norepinephrine reuptake inhibitor (NRI), was developed by Taiho Pharmaceutical Co. Ltd. and has therapeutic potential for SUI patients (Mizutani et al, 2018). A phase II randomized clinical study in SUI patients are being conducted.…”