Delving into the Latest Updates on ONO-8055 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

ONO 8055

Target

EP2 x EP3

Mechanism

EP2 agonists(Prostanoid EP2 receptor agonists), EP3 agonists(Prostanoid EP3 receptor agonists)

Therapeutic Areas

Urogenital Diseases

Active Indication-

Inactive Indication

Urinary Bladder, Underactive

Originator Organization

Ono Pharmaceutical Co., Ltd.

Active Organization-

Inactive Organization

Ono Pharmaceutical Co., Ltd.

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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Diabetic cystopathy (DC) is recognized as one of the major etiologies of underactive bladder (UAB)/detrusor underactivity (DU). Although DC was first reported about three decades ago, there is a distinct lack of effective pharmacological management methods for UAB/DU due to DC with a robust certainty of evidence. In this study, we investigated whether EP2 and EP3 receptors are promising targets of pharmacological management of UAB/DU due to DC.

Methods:

We used streptozotocin (STZ)‐induced diabetic Sprague‐Dawley rats with postvoid residual urine (PVR) greater than 0.1 mL. Sixteen weeks after induction of diabetes, we performed awake single cystometry after oral administration of the vehicle, an α‐blocker (tamsulosin [TAM], 0.1 and 0.3 mg/kg), a cholinesterase inhibitor (distigmine [DIS], 0.3 and 1.0 mg/kg), or an EP2/3 dual agonist (ONO‐8055, 0.01 and 0.03 mg/kg). We compared cystometric parameters after administration of the vehicle and drugs using a paired t test. P < .05 was considered to be statistically significant.

Results:

Compared with the vehicle, TAM significantly decreased maximum intravesical pressure during voiding (Pmax), while DIS significantly increased it. However, neither drug significantly affected PVR or the residual urine rate (RUR). On the other hand, ONO‐8055 significantly decreased PVR and tended to decrease RUR, although it did not significantly affect Pmax.

Conclusion:

The present study was unable to demonstrate that stimulation of EP2 and EP3 receptors caused major improvements in UAB/DU due to DC. However, this equivocal result could arise from inherent limitations of the STZ‐induced diabetic rat as a UAB/DU model.

01 Jan 2020·Lower urinary tract symptomsQ4 · MEDICINE

Further characterization of a novel EP2 and EP3 receptor dual agonist, ONO‐8055, on lower urinary tract function in normal and lumbar canal stenosis rats

Q4 · MEDICINE

Article

Author: Matsuya, Hidekazu ; Sekido, Noritoshi ; Mashimo, Hiroko ; Okada, Hiroki ; Kida, Jun ; Otsuki, Takeya

Abstract:

Aims:

To further explore the effects of a novel EP2 and EP3 dual agonist, ONO‐8055, on detrusor contractility, we investigated the responses of bladder strips from sham and lumbar canal stenosis (LCS) rats to this agonist, its effects on lower urinary tract function in normal rats, and mRNA expression of EP2 and EP3 receptors in the sham and LCS rats.

Methods:

The responses of bladder strips from sham and LCS rats to ONO‐8055 were measured. The effects of ONO‐8055 on LUT function of normal rats were investigated with awake cystometry and intraurethral perfusion pressure (Pura) measurements. The relative mRNA of bladder and urethral tissue of the sham and LCS rats was quantified using specific probes for EP1, EP2, EP3, and EP4 genes.

Results:

Compared with the vehicle, the muscle tensions of both the sham and LCS rats were significantly increased after adding this agonist. On awake cystometry of normal rats, bladder capacity and Pura were decreased in the ONO‐8055 groups, but a statistically significant difference in mean changes was demonstrated only between the vehicle group and the group receiving the highest dose. Compared with the sham rats, mRNA expressions of the four EP receptors in the lower urinary tract of the LCS rats did not show a statistically significant difference.

Conclusions:

This agonist did not augment bladder contractility or urethral relaxation in normal rats.

01 Jan 2018·Bioorganic & medicinal chemistryQ3 · MEDICINE

Synthesis and evaluation of a potent, well-balanced EP 2 /EP 3 dual agonist

Q3 · MEDICINE

Article

Author: Kinoshita, Akihiro ; Aratani, Yoshiyuki ; Hanada, Keisuke ; Naganawa, Atsushi ; Kakuuchi, Akito ; Higashino, Masato ; Takeda, Hiroyuki ; Matsuya, Hidekazu ; Yoshida, Koji ; Ohmoto, Kazuyuki

A highly potent and well-balanced dual agonist for the EP₂ and EP₃ receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC₅₀ EP₂ = 1.1 nM, EP₃ = 1.0 nM) with acceptable selectivity over the EP₁ and EP₄ subtypes (>2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01 mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB.

100 Deals associated with ONO-8055

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