title: Discovery and characterization of verinurad, a potent and specific inhibitor of URAT1 for the treatment of hyperuricemia and gout.
abstract: Gout is caused by elevated serum urate levels, which can be treated using inhibitors of the uric acid transporter, URAT1. Here, we characterize verinurad (RDEA3170), which is currently under evaluation for gout therapy. Verinurad specifically inhibits URAT1 with a potency of 25 nM. High affinity inhibition of uric acid transport requires URAT1 residues Cys-32, Ser-35, Phe-365 and Ile-481. Unlike other available uricosuric agents, the requirement for Cys-32 is unique to verinurad. Two of these residues, Ser-35 and Phe-365, are also important for urate transport kinetics. A URAT1 binding assay using radiolabeled verinurad revealed that distinct URAT1 inhibitors benzbromarone, sulfinpyrazone and probenecid all inhibit verinurad binding via a competitive mechanism. However, mutations made within the predicted transporter substrate channel differentially altered the potency for individual URAT1 inhibitors. Overall, our results suggest that URAT1 inhibitors bind to a common site in the core of the transporter and sterically hinder the transit of uric acid through the substrate channel, albeit with vastly different potencies and with differential interactions with specific URAT1 amino acids.
authors.affiliation: Department of Biology, Ardea Biosciences, Inc. (A member of the AstraZeneca Group), San Diego, CA, USA. ptphiltan@gmail.com.
authors.forename: Philip K
authors.initials: PK
authors.lastname: Tan
authors.affiliation: Department of Biology, Ardea Biosciences, Inc. (A member of the AstraZeneca Group), San Diego, CA, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Ardea Biosciences, Inc. (A member of the AstraZeneca Group), San Diego, CA, USA.
authors.forename: Esmir
authors.initials: E
authors.lastname: Gunic
authors.affiliation: Department of Biology, Ardea Biosciences, Inc. (A member of the AstraZeneca Group), San Diego, CA, USA.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Miner
mesh_terms: D000328:Adult; D000818:Animals; D001553:Benzbromarone / Q000494:pharmacology / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006073:Gout / Q000188:drug therapy* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D033461:Hyperuricemia / Q000188:drug therapy* / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008297:Male; D058990:Molecular Targeted Therapy; D009154:Mutation; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D014527:Uric Acid / Q000097:blood / Q000378:metabolism; D014528:Uricosuric Agents / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D014528:Uricosuric Agents; D014527:Uric Acid; D001553:Benzbromarone