CDER167,a dual inhibitor of URAT1 and GLUT9,is a novel and potent uricosuric candidate for the treatment of hyperuricemia  

作　　者：Ze-an Zhao Yu Jiang Yan-yu Chen Ting Wu Qun-sheng Lan Yong-mei Li Lu Li Yang Yang Cui-ting Lin Ying Cao Ping-zheng Zhou Jia-yin Guo Yuan-xin Tian Jian-xin Pang 

机构地区：[1]Guangdong Provincial Key Laboratory of Drug Screening,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou,510515,China

出　　处：《Acta Pharmacologica Sinica》2022年第1期121-132,共12页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(81773794 and 81974507)and the Natural Science Foundation of Guangdong Province(2018A0303130088).

摘　　要：Urate transporter 1(URAT1)and glucose transporter 9(GLUT9)are important targets for the development of uric acid-lowering drugs.We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency.In this study we designed and synthesized CDER167,a novel RDEA3710 analogue,by introducing a linker(methylene)between the naphthalene and pyridine rings to increase flexibility,and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo.We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9:CDER167 concentration-dependently inhibited the uptake of[^(14)C]-uric acid in URAT1-expressing HEK293 cells with an IC_(50) value of 2.08±0.31μM,which was similar to that of RDEA3170(its IC_(50) value was 1.47±0.23μM).Using site-directed mutagenesis,we demonstrated that CDER167 might interact with URAT1 at S35 and F365.In GLUT9-expressing HEK293T cells,CDER167 concentration-dependently inhibited GLUT9 with an IC_(50) value of 91.55±15.28μM,whereas RDEA3170 at 100μM had no effect on GLUT9.In potassium oxonate-induced hyperuricemic mice,oral administration of CDER167(10 mg·kg^(−1)·d^(−1))for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170(20 mg·kg^(−1)·d^(−1))administered.The animal experiment proved the safety of CDER167.In addition,CDER167 displayed better bioavailability than RDEA3170,better metabolic stability and no hERG toxicity at 100μM.These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.

关 键 词：GOUT HYPERURICEMIA uric acid-lowering drugs RDEA3710 CDER167 urate transporter 1(URAT1) glucose transporter 9(GLUT9) 

分 类 号：R96[医药卫生—药理学] R696[医药卫生—药学]