Author: Imazumi, Katsunori ; Masuda, Noriyuki ; Sato, Shuichi ; Noguchi, Yukiko ; Sakamoto, Kazuyuki ; Takeda, Masahiro ; Ueshima, Koji ; Ohtake, Akiyoshi

Bladder dysfunctions associated with benign prostatic hyperplasia are not sufficiently alleviated by current pharmacotherapies. Lysophosphatidic acid (LPA) is a phospholipid with diverse biological effects. LPA modulates prostate and urethral contraction via the type 1 LPA (LPA₁) receptor, suggesting the potential of the LPA₁ receptor as a therapeutic target. However, the role of LPA and the LPA₁ receptor in bladder function has not been studied in vivo. We investigated the effects of LPA and the novel LPA₁ receptor antagonist ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamido]methyl}- 1,3-thiazole-4-carbonyl)- 3-ethyl-2,2-dioxo-2λ⁶-diazathian-1-ide) on the micturition reflex in conscious rats using cystometry. Intravenous infusion of LPA decreased the micturition interval and threshold pressure with no apparent changes in baseline pressure or maximum intravesical pressure. ASP6432 inhibited the LPA-induced decrease in MI. In contrast, ASP6432 had no effect on the LPA-induced decrease in threshold pressure. Similarly, ASP6432 had no effect on either baseline pressure or maximum intravesical pressure. We also evaluated the effect of ASP6432 on the urinary frequency induced by the nitric oxide synthase inhibitor L-N^ω-nitro arginine methyl ester (L-NAME). Intravenous L-NAME administration decreased the micturition interval. ASP6432 dose-dependently reversed the L-NAME-induced decrease in micturition interval. Our findings demonstrate for the first time that LPA causes bladder overactivity in rats. ASP6432 inhibited the LPA- and L-NAME-induced decrease in micturition interval, suggesting a significant role for the LPA₁ receptor in regulating the functional capacity of the bladder. Our results also suggest the potential of ASP6432 as a novel therapy for the treatment of bladder dysfunction associated with lower urinary tract diseases.

01 Mar 2019·European Journal of PharmacologyQ3 · MEDICINE

ASP6432, a type 1 lysophosphatidic acid receptor antagonist, reduces urethral function during urine voiding and improves voiding dysfunction

Q3 · MEDICINE

Article

Author: Ohtake, Akiyoshi ; Takeda, Masahiro ; Noguchi, Yukiko ; Sakamoto, Kazuyuki ; Ueshima, Koji ; Imazumi, Katsunori ; Masuda, Noriyuki

Current pharmacotherapies for voiding dysfunctions are in need of improvement. Lysophosphatidic acid (LPA) is a phospholipid that contracts the urethra by activating type 1 LPA receptors (LPA₁). However, the role of LPA₁ in regulating urethral tonus during urine voiding which primarily affects the voiding function has not been investigated. To elucidate the role of LPA₁ in the regulation of urethral tonus during urine voiding, we investigated the effects of ASP6432, a novel LPA₁ antagonist, and the α₁-adrenoceptor antagonist tamsulosin on urethral perfusion pressure (UPP) at the filling phase (UPP_base) and the minimum UPP at the voiding phase (UPP_nadir) in anesthetized rats under isovolumetric conditions. We further evaluated the effects of ASP6432 and tamsulosin on voiding dysfunction characterized by changes in post-void residual urine (PVR) and voiding efficiency (VE) induced by the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) in conscious rats using single cystometry. ASP6432 dose-dependently decreased UPP_base and UPP_nadir, while tamsulosin reduced UPP_base but did not change UPP_nadir. ASP6432 dose-dependently suppressed the L-NAME-induced increase in PVR and decrease in VE, whereas tamsulosin did not affect either PVR or VE. We demonstrate that ASP6432 reduced UPP_nadir and ameliorated L-NAME-induced voiding dysfunction, neither of which were affected by tamsulosin. Our study results suggest that LPA₁ has a significant role in regulating urethral tonus during urine voiding, and highlight the potential of ASP6432 for improving voiding dysfunctions associated with various lower urinary tract diseases.

01 Aug 2018·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

Effect of ASP6432, a Novel Type 1 Lysophosphatidic Acid Receptor Antagonist, on Urethral Function and Prostate Cell Proliferation

Q3 · MEDICINE

Article

Author: Ohtake, Akiyoshi ; Takeda, Masahiro ; Masuda, Noriyuki ; Yamakuni, Hisashi ; Hosogai, Naomi ; Noguchi, Yukiko ; Sakamoto, Kazuyuki ; Sato, Shuichi ; Ishizu, Kenichiro ; Ueshima, Koji ; Kawaminami, Eiji

Current pharmacotherapies for lower urinary tract symptoms associated with benign prostate hyperplasia (LUTS/BPH) are in need of improvement. Lysophosphatidic acid (LPA) is a phospholipid with various biologic functions. However, its exact role in the lower urinary tract and its target receptor subtype have not been fully elucidated. We investigated the role of LPA and the type 1 LPA receptor (LPA₁) in urethral/prostatic contractile function and prostate cell proliferation by pharmacologically characterizing ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamido]methyl}-1,3-thiazole-4-carbonyl)-3-ethyl-2,2-dioxo-2λ⁶-diazathian-1-ide), a novel LPA₁ antagonist. ASP6432 exhibited potent and selective antagonistic activity against LPA₁ in cells expressing LPA receptor subtypes. In isolated rat tissue strips and anesthetized rats, ASP6432 concentration-/dose-dependently inhibited LPA-induced urethra and prostate contractions. In addition, in anesthetized rats, ASP6432 maximally decreased the urethral perfusion pressure (UPP) in the absence of exogenous LPA stimulation by 43% from baseline, whereas tamsulosin, an α₁-adrenoceptor antagonist, reduced UPP by 22%. Further, in human prostate stromal cells, ASP6432 significantly and concentration-dependently suppressed LPA-induced bromodeoxyuridine incorporation. These results demonstrate a pivotal role for LPA and LPA₁ in the regulation of urethral tonus and prostate cell proliferation. The potent urethral relaxation and inhibition of prostatic stromal cell growth indicate the potential of ASP6432 as a novel therapeutic agent for LUTS/BPH.

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Indication	Highest Phase	Country/Location	Organization	Date
Prostatic Hyperplasia	Phase 1	JP	Astellas Pharma, Inc.	-

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