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Research ArticleDrug Discovery and Translational Medicine

Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone

Sung Oh Ahn, Shuichi Ohtomo, Jumpei Kiyokawa, Toshito Nakagawa, Mizuki Yamane, Kyoung June Lee, Ki Hwan Kim, Byung Ho Kim, Jo Tanaka, Yoshiki Kawabe and Naoshi Horiba
Journal of Pharmacology and Experimental Therapeutics April 2016, 357 (1) 157-166; DOI: https://doi.org/10.1124/jpet.115.231647
Sung Oh Ahn
Discovery Research Center, C&C Research Laboratories, Suwon, Republic of Korea (S.O.A., B.H.K.); Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan (S.O., J.K, T.N., M.Y., Y.K., N.H.); Drug Discovery Center, JW Pharmaceutical Corp. Seoul, Republic of Korea (K.J.L.); JW CreaGene, Seongnam, Republic of Korea (K.H.K.); Drug Safety Research Laboratory, Shin Nihon Biological Laboratories, Miyanoura, Kagoshima, Japan (J.T.)
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Shuichi Ohtomo
Discovery Research Center, C&C Research Laboratories, Suwon, Republic of Korea (S.O.A., B.H.K.); Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan (S.O., J.K, T.N., M.Y., Y.K., N.H.); Drug Discovery Center, JW Pharmaceutical Corp. Seoul, Republic of Korea (K.J.L.); JW CreaGene, Seongnam, Republic of Korea (K.H.K.); Drug Safety Research Laboratory, Shin Nihon Biological Laboratories, Miyanoura, Kagoshima, Japan (J.T.)
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Jumpei Kiyokawa
Discovery Research Center, C&C Research Laboratories, Suwon, Republic of Korea (S.O.A., B.H.K.); Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan (S.O., J.K, T.N., M.Y., Y.K., N.H.); Drug Discovery Center, JW Pharmaceutical Corp. Seoul, Republic of Korea (K.J.L.); JW CreaGene, Seongnam, Republic of Korea (K.H.K.); Drug Safety Research Laboratory, Shin Nihon Biological Laboratories, Miyanoura, Kagoshima, Japan (J.T.)
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Toshito Nakagawa
Discovery Research Center, C&C Research Laboratories, Suwon, Republic of Korea (S.O.A., B.H.K.); Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan (S.O., J.K, T.N., M.Y., Y.K., N.H.); Drug Discovery Center, JW Pharmaceutical Corp. Seoul, Republic of Korea (K.J.L.); JW CreaGene, Seongnam, Republic of Korea (K.H.K.); Drug Safety Research Laboratory, Shin Nihon Biological Laboratories, Miyanoura, Kagoshima, Japan (J.T.)
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Mizuki Yamane
Discovery Research Center, C&C Research Laboratories, Suwon, Republic of Korea (S.O.A., B.H.K.); Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan (S.O., J.K, T.N., M.Y., Y.K., N.H.); Drug Discovery Center, JW Pharmaceutical Corp. Seoul, Republic of Korea (K.J.L.); JW CreaGene, Seongnam, Republic of Korea (K.H.K.); Drug Safety Research Laboratory, Shin Nihon Biological Laboratories, Miyanoura, Kagoshima, Japan (J.T.)
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Kyoung June Lee
Discovery Research Center, C&C Research Laboratories, Suwon, Republic of Korea (S.O.A., B.H.K.); Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan (S.O., J.K, T.N., M.Y., Y.K., N.H.); Drug Discovery Center, JW Pharmaceutical Corp. Seoul, Republic of Korea (K.J.L.); JW CreaGene, Seongnam, Republic of Korea (K.H.K.); Drug Safety Research Laboratory, Shin Nihon Biological Laboratories, Miyanoura, Kagoshima, Japan (J.T.)
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Ki Hwan Kim
Discovery Research Center, C&C Research Laboratories, Suwon, Republic of Korea (S.O.A., B.H.K.); Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan (S.O., J.K, T.N., M.Y., Y.K., N.H.); Drug Discovery Center, JW Pharmaceutical Corp. Seoul, Republic of Korea (K.J.L.); JW CreaGene, Seongnam, Republic of Korea (K.H.K.); Drug Safety Research Laboratory, Shin Nihon Biological Laboratories, Miyanoura, Kagoshima, Japan (J.T.)
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Byung Ho Kim
Discovery Research Center, C&C Research Laboratories, Suwon, Republic of Korea (S.O.A., B.H.K.); Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan (S.O., J.K, T.N., M.Y., Y.K., N.H.); Drug Discovery Center, JW Pharmaceutical Corp. Seoul, Republic of Korea (K.J.L.); JW CreaGene, Seongnam, Republic of Korea (K.H.K.); Drug Safety Research Laboratory, Shin Nihon Biological Laboratories, Miyanoura, Kagoshima, Japan (J.T.)
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Jo Tanaka
Discovery Research Center, C&C Research Laboratories, Suwon, Republic of Korea (S.O.A., B.H.K.); Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan (S.O., J.K, T.N., M.Y., Y.K., N.H.); Drug Discovery Center, JW Pharmaceutical Corp. Seoul, Republic of Korea (K.J.L.); JW CreaGene, Seongnam, Republic of Korea (K.H.K.); Drug Safety Research Laboratory, Shin Nihon Biological Laboratories, Miyanoura, Kagoshima, Japan (J.T.)
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Yoshiki Kawabe
Discovery Research Center, C&C Research Laboratories, Suwon, Republic of Korea (S.O.A., B.H.K.); Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan (S.O., J.K, T.N., M.Y., Y.K., N.H.); Drug Discovery Center, JW Pharmaceutical Corp. Seoul, Republic of Korea (K.J.L.); JW CreaGene, Seongnam, Republic of Korea (K.H.K.); Drug Safety Research Laboratory, Shin Nihon Biological Laboratories, Miyanoura, Kagoshima, Japan (J.T.)
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Naoshi Horiba
Discovery Research Center, C&C Research Laboratories, Suwon, Republic of Korea (S.O.A., B.H.K.); Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan (S.O., J.K, T.N., M.Y., Y.K., N.H.); Drug Discovery Center, JW Pharmaceutical Corp. Seoul, Republic of Korea (K.J.L.); JW CreaGene, Seongnam, Republic of Korea (K.H.K.); Drug Safety Research Laboratory, Shin Nihon Biological Laboratories, Miyanoura, Kagoshima, Japan (J.T.)
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Abstract

Urate-lowering therapy is indispensable for the treatment of gout, but available drugs do not control serum urate levels tightly enough. Although the uricosurics benzbromarone and probenecid inhibit a urate reabsorption transporter known as renal urate transporter 1 (URAT1) and thus lower serum urate levels, they also inhibit other transporters responsible for secretion of urate into urine, which suggests that inhibiting URAT1 selectively would lower serum urate more effectively. We identified a novel potent and selective URAT1 inhibitor, UR-1102, and compared its efficacy with benzbromarone in vitro and in vivo. In human embryonic kidney (HEK)293 cells overexpressing URAT1, organic anion transporter 1 (OAT1), and OAT3, benzbromarone inhibited all transporters similarly, whereas UR-1102 inhibited URAT1 comparably to benzbromarone but inhibited OAT1 and OAT3 quite modestly. UR-1102 at 3–30 mg/kg or benzbromarone at 3–100 mg/kg was administered orally once a day for 3 consecutive days to tufted capuchin monkeys, whose low uricase activity causes a high plasma urate level. When compared with the same dosage of benzbromarone, UR-1102 showed a better pharmacokinetic profile, increased the fractional excretion of urinary uric acid, and reduced plasma uric acid more effectively. Moreover, the maximum efficacy of UR-1102 was twice that of benzbromarone, suggesting that selective inhibition of URAT1 is effective. Additionally UR-1102 showed lower in vitro potential for mechanisms causing the hepatotoxicity induced by benzbromarone. These results indicate that UR-1102 achieves strong uricosuric effects by selectively inhibiting URAT1 over OAT1 and OAT3 in monkeys, and could be a novel therapeutic option for patients with gout or hyperuricemia.

Footnotes

    • Received December 21, 2015.
    • Accepted February 11, 2016.
  • Primary laboratory of origin: C&C Research Laboratories.

  • Results of this study were presented in part as: Ahn SO, Horiba N, Ohtomo S, Lee KJ, Kim KH, Kim BH, Kiyokawa J, Yamane M, Ikegami H, Nakagawa T, et al. (2013) The therapeutic efficacy of the novel uricosuric agent UR-1102 for hyperuricemia and gout. Annual European Congress of Rheumatology; June 2013; Madrid, Spain. Abstr. no. SAT0356, The European League Against Rheumatism (EULAR), Kilchberg, Switzerland; published as Ann Rheum Dis 72 (suppl. 3):704.

  • dx.doi.org/10.1124/jpet.115.231647.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 357 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 357, Issue 1
1 Apr 2016
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Research ArticleDrug Discovery and Translational Medicine

Novel Urate-Lowering Drug UR-1102 for Cebus Monkeys

Sung Oh Ahn, Shuichi Ohtomo, Jumpei Kiyokawa, Toshito Nakagawa, Mizuki Yamane, Kyoung June Lee, Ki Hwan Kim, Byung Ho Kim, Jo Tanaka, Yoshiki Kawabe and Naoshi Horiba
Journal of Pharmacology and Experimental Therapeutics April 1, 2016, 357 (1) 157-166; DOI: https://doi.org/10.1124/jpet.115.231647

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Research ArticleDrug Discovery and Translational Medicine

Novel Urate-Lowering Drug UR-1102 for Cebus Monkeys

Sung Oh Ahn, Shuichi Ohtomo, Jumpei Kiyokawa, Toshito Nakagawa, Mizuki Yamane, Kyoung June Lee, Ki Hwan Kim, Byung Ho Kim, Jo Tanaka, Yoshiki Kawabe and Naoshi Horiba
Journal of Pharmacology and Experimental Therapeutics April 1, 2016, 357 (1) 157-166; DOI: https://doi.org/10.1124/jpet.115.231647
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