A novel highly potent autotaxin/ENPP2 inhibitor produces prolonged decreases in plasma lysophosphatidic acid formation in vivo and regulates urethral tension

Hiroshi Saga, Akira Ohhata, Akio Hayashi, Makoto Katoh, Tatsuo Maeda, Hirotaka Mizuno, Yuka Takada, Yuka Komichi, Hiroto Ota, Naoya Matsumura, Masami Shibaya, Tetsuya Sugiyama, Shinji Nakade, Katsuya Kishikawa

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted enzyme that has lysophospholipase D activity, which converts lysophosphatidylcholine to bioactive lysophosphatidic acid. Lysophosphatidic acid activates at least six G-protein coupled recpetors, which promote cell proliferation, survival, migration and muscle contraction. These physiological effects become dysfunctional in the pathology of cancer, fibrosis, and pain. To date, several autotaxin/ENPP2 inhibitors have been reported; however, none were able to completely and continuously inhibit autotaxin/ENPP2 in vivo. In this study, we report the discovery of a highly potent autotaxin/ENPP2 inhibitor, ONO-8430506, which decreased plasma lysophosphatidic acid formation. The IC50 values of ONO-8540506 for lysophospholipase D activity were 6.4-19 nM for recombinant autotaxin/ENPP2 proteins and 4.7-11.6 nM for plasma from various animal species. Plasma lysophosphatidic acid formation during 1-h incubation was almost completely inhibited by the addition of >300 nM of the compound to human plasma. In addition, when administered orally to rats at a dose of 30 mg/kg, the compound demonstrated good pharmacokinetics in rats and persistently inhibited plasma lysophosphatidic acid formation even at 24 h after administration. Smooth muscle contraction is a known to be promoted by lysophosphatidic acid. In this study, we showed that dosing rats with ONO-8430506 decreased intraurethral pressure accompanied by urethral relaxation. These findings demonstrate the potential of this autotaxin/ENPP2 inhibitor for the treatment of various diseases caused by lysophosphatidic acid, including urethral obstructive disease such as benign prostatic hyperplasia.

Original languageEnglish
Article numbere93230
JournalPloS one
Volume9
Issue number4
DOIs
Publication statusPublished - 2014 Apr 18

ASJC Scopus subject areas

  • General

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