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

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.

01 Aug 2016·Journal of UrologyQ1 · MEDICINE

Promising Effects of a Novel EP2 and EP3 Receptor Dual Agonist, ONO-8055, on Neurogenic Underactive Bladder in a Rat Lumbar Canal Stenosis Model

Q1 · MEDICINE

Article

Author: Sekido, Noritoshi ; Kida, Jun ; Wakamatsu, Daisuke ; Okada, Hiroki ; Matsuya, Hidekazu ; Mashimo, Hiroko

PURPOSEWe investigated whether the novel EP (prostaglandin E2) receptor agonist ONO-8055 would improve the lower urinary tract dysfunction of neurogenic underactive bladder in a rat lumbar spinal canal stenosis model.MATERIALS AND METHODSFirst, we studied the agonistic effect of ONO-8055 on EP receptors in EP receptor expressing CHO (Chinese hamster ovary) cells using the increase in the intracellular calcium level and intracellular cAMP (cyclic adenosine monophosphate) production as indicators of receptor activation. The effects of ONO-8055 on bladder and urethral strips from normal rats were then investigated. Finally, the effects of ONO-8055 on bladder and urethral function in rats with lumbar spinal canal stenosis were evaluated by awake cystometry and intraurethral perfusion pressure, respectively. The effects of tamsulosin and distigmine on urethral pressure were also evaluated.RESULTSONO-8055 is a highly potent and selective agonist for EP2 and EP3 receptors on CHO cells. While this compound contracted bladder strips, it relaxed urethral strips. Awake cystometry showed that ONO-8055 significantly decreased bladder capacity, post-void residual urine and voiding pressure. Compared with vehicle, tamsulosin and ONO-8055 significantly decreased urethral pressure.CONCLUSIONSONO-8055 decreased post-void residual urine, probably by decreasing bladder capacity. The decrease in voiding pressure probably resulted from the lowered urethral pressure due to relaxation of the urethra. Thus, the novel EP2 and EP3 receptor dual agonist ONO-8055 has the potential to improve neurogenic underactive bladder.

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Indication	Highest Phase	Country/Location	Organization	Date
Urinary Bladder, Underactive	Phase 1	Europe	Ono Pharmaceutical Co., Ltd.	-
Urinary Bladder, Underactive	Phase 1	Japan	Ono Pharmaceutical Co., Ltd.	-
Urinary Bladder, Underactive	Phase 1	Japan	Ono Pharmaceutical Co., Ltd.	-
Urinary Bladder, Underactive	Phase 1	Europe	Ono Pharmaceutical Co., Ltd.	-

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