2. Academic Validation
  3. Discovery of novel Bruton's tyrosine kinase (BTK) inhibitors bearing a pyrrolo[2,3-d]pyrimidine scaffold

Discovery of novel Bruton's tyrosine kinase (BTK) inhibitors bearing a pyrrolo[2,3-d]pyrimidine scaffold

  • Bioorg Med Chem. 2015 Feb 15;23(4):891-901. doi: 10.1016/j.bmc.2014.10.043.
Xinge Zhao 1,  Wei Huang 2,  Yazhou Wang 3,  Minhang Xin 4,  Qiu Jin 3,  Jianfeng Cai 3,  Feng Tang 3,  Yong Zhao 3,  Hua Xiang 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
  • 2 Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, No 152, Luoyu Road, Wuhan 430079, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
  • 3 Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No 76, Yanta West Road, Xi'an 710061, PR China.
  • 5 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, PR China. Electronic address: xianghua@cpu.edu.cn.
PMID: 25596757 DOI: 10.1016/j.bmc.2014.10.043
Abstract

A series of novel reversible Btk inhibitors was designed based on the structure of the recently reported preclinical drug RN486. Knowledge of the binding mode of RN486 led to the design of new inhibitors that utilized pyrrolo[2,3-d]pyrimidine to conformationally restrain key pharmacophoric groups within the molecule. Comprehensive SAR was disclosed and the most promising compound 4x displayed superior activity both in BTK Enzyme (IC50=4.8nM) and cellular inhibition (IC50=17nM) assays to that of RN486.

Keywords

BTK inhibitors; Pyrrolo[23-d]pyrimidine; SAR.

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