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.
Jianbiao Peng  1 ,  Qiyue Hu  2 ,  Chunyan Gu  2 ,  Bonian Liu  2 ,  Fangfang Jin  2 ,  Jijun Yuan  2 ,  Jun Feng  2 ,  Lei Zhang  2 ,  Jiong Lan  2 ,  Qing Dong  2 ,  Guoqing Cao  2
Affiliations
  • 1. Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China. Electronic address: [email protected].
  • 2. Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China.
PMID: 26704267 DOI: 10.1016/j.bmcl.2015.12.040
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.