Discovery of potent and orally bioavailable inhibitors of Human Uric Acid Transporter 1 (hURAT1) and binding mode prediction using homology model

Bioorg Med Chem Lett. 2016 Jan 15;26(2):277-282. doi: 10.1016/j.bmcl.2015.12.040. Epub 2015 Dec 12.

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).

Keywords: 3D pharmacophore; Gout; Hyperuricemia; URAT1 homology model; URAT1 inhibitors.

MeSH terms

  • Animals
  • Cyclobutanes / chemical synthesis
  • Cyclobutanes / pharmacokinetics
  • Cyclobutanes / pharmacology*
  • Dogs
  • Gout Suppressants / chemical synthesis
  • Gout Suppressants / pharmacokinetics
  • Gout Suppressants / pharmacology*
  • Humans
  • Macaca fascicularis
  • Microsomes, Liver / metabolism
  • Molecular Docking Simulation
  • Organic Anion Transporters / antagonists & inhibitors*
  • Organic Anion Transporters / chemistry
  • Organic Cation Transport Proteins / antagonists & inhibitors*
  • Organic Cation Transport Proteins / chemistry
  • Quinolines / chemical synthesis
  • Quinolines / pharmacokinetics
  • Quinolines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structural Homology, Protein
  • Structure-Activity Relationship

Substances

  • 1-((6-bromoquinolin-4-yl)thio)cyclobutanecarboxylic acid
  • Cyclobutanes
  • Gout Suppressants
  • Organic Anion Transporters
  • Organic Cation Transport Proteins
  • Quinolines
  • SLC22A12 protein, human