title: A novel highly potent autotaxin/ENPP2 inhibitor produces prolonged decreases in plasma lysophosphatidic acid formation in vivo and regulates urethral tension.
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.
authors.affiliation: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saga
authors.affiliation: Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohhata
authors.affiliation: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Katoh
authors.affiliation: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Mizuno
authors.affiliation: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Takada
authors.affiliation: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Komichi
authors.affiliation: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ota
authors.affiliation: Discovery Technology Laboratories, ONO Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsumura
authors.affiliation: Safety Research Laboratories, ONO Phamaceutical Co., Ltd., Sakai, Fukui, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Shibaya
authors.affiliation: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakade
authors.affiliation: Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Kishikawa
mesh_terms: D000818:Animals; D002243:Carbolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008246:Lysophospholipids / Q000096:biosynthesis* / Q000097:blood*; D008297:Male; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011312:Pressure; D051381:Rats; D013997:Time Factors; D014521:Urethra / Q000187:drug effects* / Q000502:physiology*; D000099189:Lysophospholipase D
chemical_list: D002243:Carbolines; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D; C000592118:ONO-8430506; C032881:lysophosphatidic acid
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