Synthesis and evaluation of sulfonamide derivatives as potent Human Uric Acid Transporter 1 (hURAT1) inhibitors

Xintuo Yang; Xuehai Pang; Lei Fan; Xinghai Li; Yuanwei Chen

doi:10.1016/j.bmcl.2017.03.041

Synthesis and evaluation of sulfonamide derivatives as potent Human Uric Acid Transporter 1 (hURAT1) inhibitors

Bioorg Med Chem Lett. 2017 May 1;27(9):1919-1922. doi: 10.1016/j.bmcl.2017.03.041. Epub 2017 Mar 18.

Authors

Xintuo Yang¹, Xuehai Pang¹, Lei Fan², Xinghai Li², Yuanwei Chen³

Affiliations

¹ Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, Sichuan 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² Hinova Pharmaceuticals Inc., Suite 301, Building B, #5 South KeYuan Road, Chengdu, Sichuan 610041, China.
³ Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, Sichuan 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China; Hinova Pharmaceuticals Inc., Suite 301, Building B, #5 South KeYuan Road, Chengdu, Sichuan 610041, China. Electronic address: ywchen@scu.edu.cn.

PMID: 28351592
DOI: 10.1016/j.bmcl.2017.03.041

Abstract

This letter presents synthesis and structure-activity relationship study of sulfonamide derivatives as inhibitors of Human Uric Acid Transporter 1 (hURAT1). Among all tested sulfonamide derivatives, compounds 9b, 16i and 19b exhibited excellent inhibition activity with IC₅₀ value of 10, 2, and 83nM, respectively. In addition, compounds 9b and 19b demonstrated moderate PK profile in rats.

Keywords: Bioisostere; Gout disease; Pharmacokinetic studies; Structure-activity relationship; Sulfonamide; hURAT1 inhibitor.

MeSH terms

Animals
Gout / drug therapy
Gout / enzymology
Gout Suppressants / chemical synthesis
Gout Suppressants / chemistry*
Gout Suppressants / pharmacokinetics
Gout Suppressants / pharmacology*
Humans
Male
Organic Anion Transporters / antagonists & inhibitors*
Organic Anion Transporters / metabolism
Organic Cation Transport Proteins / antagonists & inhibitors*
Organic Cation Transport Proteins / metabolism
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / pharmacokinetics
Sulfonamides / pharmacology*

Substances

Gout Suppressants
Organic Anion Transporters
Organic Cation Transport Proteins
SLC22A12 protein, human
Sulfonamides