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  3. Proline-derived quinoline formamide compounds as human urate transporter 1 inhibitors with potent uric acid-lowering activities

Proline-derived quinoline formamide compounds as human urate transporter 1 inhibitors with potent uric acid-lowering activities

  • Eur J Med Chem. 2024 Apr 5:269:116327. doi: 10.1016/j.ejmech.2024.116327.
Shengnan Li 1,  Hui Liao 2,  Lijun Luo 1,  Bingxu Meng 1,  Fengxin Zheng 2,  Li Sheng 1,  Hongyi Zhao 1,  Yi Huan 1,  Lei Lei 1,  Jiayu Zhai 1,  Kunlu Zhao 2,  Jinhong Tian 2,  Ting Wu 2,  Gang Li 3,  Jianxin Pang 4,  Haihong Huang 5
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, PR China.
  • 2 NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China.
  • 3 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, PR China. Electronic address: ligang@imm.ac.cn.
  • 4 NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China. Electronic address: pjx@smu.edu.cn.
  • 5 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, PR China. Electronic address: joyce@imm.ac.cn.
PMID: 38547733 DOI: 10.1016/j.ejmech.2024.116327
Abstract

We report the design and synthesis of a series of proline-derived quinoline formamide compounds as human urate transporter 1 (URAT1) inhibitors via a ligand-based pharmacophore approach. Structure-activity relationship studies reveal that the replacement of the carboxyl group on the polar fragment with trifluoromethanesulfonamide and substituent modification at the 6-position of the quinoline ring greatly improve URAT1 inhibitory activity compared with lesinurad. Compounds 21c, 21e, 24b, 24c, and 23a exhibit potent activities against URAT1 with IC50 values ranging from 0.052 to 0.56 μM. Furthermore, compound 23a displays improved selectivity towards organic anion transporter 1 (OAT1), good microsomal stability, low potential for genotoxicity and no inhibition of the hERG K+ channel. Compounds 21c and 23a, which have superior pharmacokinetic properties, also demonstrate significant uric acid-lowering activities in a mouse model of hyperuricemia. Notably, 21c also exhibits moderate anti-inflammatory activity related to the gout inflammatory pathway. Compounds 21c and 23a with superior druggability are potential candidates for the treatment of hyperuricemia and gout.

Keywords

Anti-inflammatory activity; Druggability; Hyperuricemia; Quinoline formamides; URAT1.

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