Tags

Type your tag names separated by a space and hit enter

Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone.
J Pharmacol Exp Ther. 2016 Apr; 357(1):157-66.JP

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.

Authors+Show Affiliations

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.).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.).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.).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.).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.).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.).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.).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.).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.).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.).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.) horibanos@chugai-pharm.co.jp.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26907620

Citation

Ahn, Sung Oh, et al. "Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent Than Benzbromarone." The Journal of Pharmacology and Experimental Therapeutics, vol. 357, no. 1, 2016, pp. 157-66.
Ahn SO, Ohtomo S, Kiyokawa J, et al. Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone. J Pharmacol Exp Ther. 2016;357(1):157-66.
Ahn, S. O., Ohtomo, S., Kiyokawa, J., Nakagawa, T., Yamane, M., Lee, K. J., Kim, K. H., Kim, B. H., Tanaka, J., Kawabe, Y., & Horiba, N. (2016). Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone. The Journal of Pharmacology and Experimental Therapeutics, 357(1), 157-66. https://doi.org/10.1124/jpet.115.231647
Ahn SO, et al. Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent Than Benzbromarone. J Pharmacol Exp Ther. 2016;357(1):157-66. PubMed PMID: 26907620.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone. AU - Ahn,Sung Oh, AU - Ohtomo,Shuichi, AU - Kiyokawa,Jumpei, AU - Nakagawa,Toshito, AU - Yamane,Mizuki, AU - Lee,Kyoung June, AU - Kim,Ki Hwan, AU - Kim,Byung Ho, AU - Tanaka,Jo, AU - Kawabe,Yoshiki, AU - Horiba,Naoshi, Y1 - 2016/02/23/ PY - 2015/12/21/received PY - 2016/02/11/accepted PY - 2016/2/25/entrez PY - 2016/2/26/pubmed PY - 2016/7/20/medline SP - 157 EP - 66 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 357 IS - 1 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/26907620/Stronger_Uricosuric_Effects_of_the_Novel_Selective_URAT1_Inhibitor_UR_1102_Lowered_Plasma_Urate_in_Tufted_Capuchin_Monkeys_to_a_Greater_Extent_than_Benzbromarone_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=26907620 DB - PRIME DP - Unbound Medicine ER -