Discovery of 4-Aminoquinoline-3-carboxamide Derivatives as Potent Reversible Bruton's Tyrosine Kinase Inhibitors for the Treatment of Rheumatoid Arthritis

  • J Med Chem. 2019 Jul 25;62(14):6561-6574. doi: 10.1021/acs.jmedchem.9b00329.
Xia Yao  1 ,  Xiuyun Sun  1  2 ,  Shuyu Jin  3 ,  Ling Yang  4 ,  Hongjiang Xu  4 ,  Yu Rao  1
Affiliations
  • 1. Ministry of Education (MOE) Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology , Tsinghua University , Beijing 100084 , P. R. China.
  • 2. Tsinghua-Peking Center for Life Sciences , Beijing 100084 , P. R. China.
  • 3. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education , Shenyang Pharmaceutical University , Shenyang 110016 , P. R. China.
  • 4. R&D Institute , Chia Tai Tianqing Pharmaceutical Group Co., LTD , Nanjing 210023 , P. R. China.
PMID: 31260299 DOI: 10.1021/acs.jmedchem.9b00329
Abstract

A structure-hopping strategy was applied to discover a series of novel 4-aminoquinoline-3-carboxamide derivatives as potent, reversible Btk inhibitors. Compared to the previously described cinnoline scaffold compounds, the 4-aminoquinoline analogues showed significantly improved drug-like properties, especially in their aqueous solubility. The most potent compound, 25, displayed a stronger inhibitory effect on both BtkWT (IC50 = 5.3 nM) and BtkC481S (IC50 = 39 nM). In a rodent collagen-induced arthritis model, compound 25 efficiently reduced paw swelling without a loss in body weight. On the basis of potency, drug-like properties, stability, and noncovalent mode of inhibition, our representative inhibitors could have a promising profile to be treatments for a wide range of autoimmune diseases.

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