Approaching the active conformation of 1,3-diaminopyrimidine based covalent inhibitors of Bruton's tyrosine kinase for treatment of Rheumatoid arthritis

  • Bioorg Med Chem Lett. 2016 Apr 15;26(8):1954-7. doi: 10.1016/j.bmcl.2016.03.011.
Zhenhua Huang  1 ,  Qian Zhang  2 ,  Lianzhong Yan  2 ,  Guizhen Zhong  2 ,  Linqi Zhang  2 ,  Xiaojuan Tan  2 ,  Yanli Wang  2
Affiliations
  • 1. KBP Biosciences, C201, No. 750, Shunhua Road, Jinan, Shandong Province 250101, China. Electronic address: [email protected].
  • 2. KBP Biosciences, C201, No. 750, Shunhua Road, Jinan, Shandong Province 250101, China.
PMID: 26976214 DOI: 10.1016/j.bmcl.2016.03.011
Abstract

By applying conformational restrictions, we were able to discover highly potent 1,3-diaminopyrimidine based covalent inhibitors of Btk, such as 8a (IC50=3.76 nM), and providing useful information of its active conformation. We are developing these novel small molecule covalent inhibitors of Btk toward oral agents for Rheumatoid arthritis.

Keywords
1,3-Diamino-pyrimidine; Bruton’s tyrosine kinase (BTK); Collagen-induced arthritis (CIA); Rheumatoid arthritis (RA).