title: Discovery of a Flexible Triazolylbutanoic Acid as a Highly Potent Uric Acid Transporter 1 (URAT1) Inhibitor.
abstract: In order to systematically explore and understand the structure-activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH₂, 18 compounds (1a-1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor,1q, which was 31-fold more potent than parent lesinurad (IC50= 0.23 μM against human URAT1 for1qvs 7.18 μM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China. tian_he9562@hotmail.com.|Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. tian_he9562@hotmail.com.
authors.forename: He
authors.initials: H
authors.lastname: Tian
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. liuw@tjipr.com.
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. zhouzx@tjipr.com.
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. shangq@tjipr.com.
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. liuyq@tjipr.com.
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. xieyf@tjipr.com.
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. liucy@tjipr.com.
authors.forename: Changying
authors.initials: C
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. xuwr@tjipr.com.
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. tangld@tjipr.com.
authors.forename: Lida
authors.initials: L
authors.lastname: Tang
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China. jwwang@sdu.edu.cn.
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, Tianjin 300193, China. zhao_guilong@126.com.
authors.forename: Guilong
authors.initials: G
authors.lastname: Zhao
mesh_terms: D020148:Butyric Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*
chemical_list: D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D020148:Butyric Acid
keywords: URAT1 inhibitor; gout; hyperuricemia; lesinurad; synthesis