title: Discovery of potent and orally bioavailable inhibitors of Human Uric Acid Transporter 1 (hURAT1) and binding mode prediction using homology model.
abstract: This Letter describes the discovery of a series of potent inhibitors of Human Uric Acid Transporter 1 (hURAT1). Lead generation and optimization via 3D pharmacophore analysis resulted in compound 41. With an IC50 of 33.7nM, 41 also demonstrated good oral bioavailability in rat (74.8%) and displayed a consistent PK profile across all species tested (rat, dog and monkey).
authors.affiliation: Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China. Electronic address: pengjb@shhrp.com.
authors.forename: Jianbiao
authors.initials: J
authors.lastname: Peng
authors.affiliation: Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China.
authors.forename: Qiyue
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Gu
authors.affiliation: Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China.
authors.forename: Bonian
authors.initials: B
authors.lastname: Liu
authors.affiliation: Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Jin
authors.affiliation: Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China.
authors.forename: Jijun
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Lan
authors.affiliation: Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Cao
mesh_terms: D000818:Animals; D003503:Cyclobutanes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D006074:Gout Suppressants / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000737:chemistry; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011804:Quinolines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: C000613562:1-((6-bromoquinolin-4-yl)thio)cyclobutanecarboxylic acid; D003503:Cyclobutanes; D006074:Gout Suppressants; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D011804:Quinolines; C491241:SLC22A12 protein, human
keywords: 3D pharmacophore; Gout; Hyperuricemia; URAT1 homology model; URAT1 inhibitors