2. Academic Validation
  3. Design, synthesis and evaluation of pyrrolo[2,3-d]pyrimidine-phenylamide hybrids as potent Janus kinase 2 inhibitors

Design, synthesis and evaluation of pyrrolo[2,3-d]pyrimidine-phenylamide hybrids as potent Janus kinase 2 inhibitors

  • Bioorg Med Chem Lett. 2016 Jun 15;26(12):2936-2941. doi: 10.1016/j.bmcl.2016.04.027.
Tingfang Wang 1,  Xiaofei Liu 1,  Meixi Hao 1,  Jianan Qiao 1,  Caoyun Ju 1,  Lingjing Xue 2,  Can Zhang 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
  • 2 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: xuelingjing65@163.com.
  • 3 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: zhangcan@cpu.edu.cn.
PMID: 27130359 DOI: 10.1016/j.bmcl.2016.04.027
Abstract

Janus kinase 2 (JAK2) plays an essential role in the signaling of hormone-like Cytokines and Growth Factors, which has been convinced as an important target of myeloproliferative neoplasms (MPNs) therapy. In this study, a series of novel pyrrolo[2,3-d]pyrimidine-phenylamide hybrids were designed and synthesized as potential JAK2 inhibitors through hybridization strategy. In vitro biological studies showed that most of these compounds exhibited potent activity against JAK2. Especially, compound 16c was identified as a suitable lead compound, which showed favorable pharmacokinetic profiles in rats (F=73.57%), excellent in vitro efficacy against erythroleukemic cells (TF-1, IC50=0.14μM), and high selectivity for JAK2 (IC50=6nM with >97-fold selectivity vs JAK3).

Keywords

Hybridization; JAK2 inhibitors; Myeloproliferative neoplasms; Pyrrolo[2,3-d]pyrimidine.

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