2. Academic Validation
  3. Discovery of potent anti-inflammatory 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl) pyrimidin-2-amines for use as Janus kinase inhibitors

Discovery of potent anti-inflammatory 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl) pyrimidin-2-amines for use as Janus kinase inhibitors

  • Bioorg Med Chem. 2019 Jun 15;27(12):2592-2597. doi: 10.1016/j.bmc.2019.03.048.
Yazhou Wang 1,  Wei Huang 2,  Minhang Xin 3,  Pan Chen 4,  Li Gui 4,  Xinxin Zhao 4,  Xinrong Zhu 5,  Hongpeng Luo 5,  Xin Cong 5,  Jia Wang 5,  Fei Liu 6
Affiliations

Affiliations

  • 1 Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuanwu District, Nanjing 210042, PR China. Electronic address: [email protected].
  • 2 Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuanwu District, Nanjing 210042, PR China. Electronic address: [email protected].
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No 76, Yanta West Road, Xi'an 710061, PR China.
  • 4 Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuanwu District, Nanjing 210042, PR China; Nanjing Noratech Pharmaceutical Co. Ltd., No 9 Weidi Road, Jiangsu Life Park, Qixia District, Nanjing 210046, PR China.
  • 5 Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuanwu District, Nanjing 210042, PR China.
  • 6 Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuanwu District, Nanjing 210042, PR China; Nanjing Noratech Pharmaceutical Co. Ltd., No 9 Weidi Road, Jiangsu Life Park, Qixia District, Nanjing 210046, PR China. Electronic address: [email protected].
PMID: 30926315 DOI: 10.1016/j.bmc.2019.03.048
Abstract

The Janus kinase (JAK) family of tyrosine kinases has been proven to provide targeted immune modulation. Orally available JAK inhibitors have been used for the treatment of immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). Here, we report the design, synthesis and biological evaluation of 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl) pyrimidin-2-amino derivatives as JAK inhibitors. Systematic structure-activity relationship studies led to the discovery of compound 7j, which strongly inhibited the four isoforms of JAK kinases. Molecular modeling rationalized the importance of cyanoacetyl and phenylmorpholine moieties. The in vivo investigation indicated that compound 7j possessed favorable pharmacokinetic properties and displayed slightly better anti-inflammatory efficacy than tofacitinib at the same dosage. Accordingly, compound 7j was advanced into preclinical development.

Keywords

Anti-inflammatory; Furo[3,2-c]pyridine; JAK inhibitor; Rheumatoid arthritis.

Figures