title: Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone.
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.affiliation: 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.).
authors.forename: Sung Oh
authors.initials: SO
authors.lastname: Ahn
authors.affiliation: 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.).
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ohtomo
authors.affiliation: 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.).
authors.forename: Jumpei
authors.initials: J
authors.lastname: Kiyokawa
authors.affiliation: 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.).
authors.forename: Toshito
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: 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.).
authors.forename: Mizuki
authors.initials: M
authors.lastname: Yamane
authors.affiliation: 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.).
authors.forename: Kyoung June
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: 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.).
authors.forename: Ki Hwan
authors.initials: KH
authors.lastname: Kim
authors.affiliation: 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.).
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Kim
authors.affiliation: 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.).
authors.forename: Jo
authors.initials: J
authors.lastname: Tanaka
authors.affiliation: 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.).
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kawabe
authors.affiliation: 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.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Horiba
mesh_terms: D000818:Animals; D001553:Benzbromarone / Q000494:pharmacology*; D002428:Cebus; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000096:biosynthesis / Q000235:genetics; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D010078:Oxazines / Q000494:pharmacology*; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology*; D014527:Uric Acid / Q000097:blood; D014528:Uricosuric Agents / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D010078:Oxazines; D011725:Pyridines; C491241:SLC22A12 protein, human; C000609144:UR-1102; D014528:Uricosuric Agents; C114338:organic anion transport protein 3; D014527:Uric Acid; D001553:Benzbromarone