title: Discovery of Flexible Naphthyltriazolylmethane-based Thioacetic Acids as Highly Active Uric Acid Transporter 1 (URAT1) Inhibitors for the Treatment of Hyperuricemia of Gout.
abstract: BACKGROUND
  Gout is the most common inflammatory arthritis, which, if left untreated or inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering therapy.
  
  
  OBJECTIVE
  The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropyl-naphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor.
  
  
  METHODS
  The SAR of 1c was systematically explored and the in vitro URAT1 inhibitory activity of synthesized compounds 1a-1t was determined by the inhibition of URAT1-mediated [8-14C]uric acid uptake by human embryonic kidney 293 (HEK293) cells stably expressing human URAT1.
  
  
  RESULTS
  Twenty compounds 1a-1t were synthesized. SAR analysis was performed. Two highly active URAT1 inhibitors, sodium 2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1j) and sodium 2-((5-bromo-4-((4-bromonaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1m), were identified, which were 78- and 76-fold more active than parent lesinurad in in vitro URAT1 inhibitory assay, respectively (IC50 values for 1j and 1m were 0.092 μM and 0.094 μM, respectively, against human URAT1 vs 7.18 μM for lesinurad).
  
  
  CONCLUSIONS
  Two highly active URAT1 inhibitors were discovered. The SAR exploration also identified more flexible naphthyltriazolylmethane as a novel molecular skeleton that will be valuable for the design of URAT1 inhibitors, as indicated by the observation that many of the synthesized naphthyltriazolylmethane- bearing derivatives (1b-1d, 1g, 1j and 1m) showed significantly improved UART1 inhibitory activity (sub-micromolar IC50 values) as compared with lesinurad which has the rigid naphthyltriazole skeleton.
authors.affiliation: Shandong Lukang Pharmaceutical Co., Ltd., Jining 272021, China.
authors.forename: Xiansheng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Wu
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shang
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors.forename: Zhixing
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors.forename: Weiren
authors.initials: W
authors.lastname: Xu
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors.forename: Lida
authors.initials: L
authors.lastname: Tang
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.
authors.forename: Jianwu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, 308 An Shan Xi Dao, Nankai District, Tianjin 300193, China.
authors.forename: Guilong
authors.initials: G
authors.lastname: Zhao
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006073:Gout / Q000188:drug therapy*; D057809:HEK293 Cells; D006801:Humans; D033461:Hyperuricemia / Q000188:drug therapy*; D015394:Molecular Structure; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000622100:2-((5-bromo-4-((4-bromonaphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetic acid; C000622098:2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetic acid; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D013438:Sulfhydryl Compounds; D014230:Triazoles; C005732:thioacetic acid
keywords: Gout; URAT1 inhibitor; flexible; hyperuricemia; lesinurad; synthesis