2. Academic Validation
  3. Design and synthesis of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine as a highly potent and selective cyclin-dependent kinases 4 and 6 inhibitors and the discovery of structure-activity relationships

Design and synthesis of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine as a highly potent and selective cyclin-dependent kinases 4 and 6 inhibitors and the discovery of structure-activity relationships

  • Bioorg Med Chem Lett. 2018 Mar 1;28(5):974-978. doi: 10.1016/j.bmcl.2017.12.068.
Yan Wang 1,  Wen-Jian Liu 2,  Lei Yin 2,  Heng Li 2,  Zhen-Hua Chen 2,  Dian-Xi Zhu 2,  Xiu-Qing Song 3,  Zhen-Zhen Cheng 2,  Peng Song 3,  Zhan Wang 4,  Zhi-Gang Li 5
Affiliations

Affiliations

  • 1 Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry and Chemical Engineering, Beijing University of Technology, Beijing 100124, PR China; Gan&lee Pharmaceuticals R&D, No.8 Jingsheng North 3rd Street, Majuqiao Town, Tongzhou, Beijing 101102, PR China.
  • 2 Gan&lee Pharmaceuticals R&D, No.8 Jingsheng North 3rd Street, Majuqiao Town, Tongzhou, Beijing 101102, PR China.
  • 3 Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry and Chemical Engineering, Beijing University of Technology, Beijing 100124, PR China.
  • 4 Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry and Chemical Engineering, Beijing University of Technology, Beijing 100124, PR China. Electronic address: wangzh@bjut.edu.cn.
  • 5 Beijing Handian Pharmaceutical Co. Ltd., Kuntai International Building, Chaoyang, Beijing 100020, PR China. Electronic address: lizhigang@handian.com.
PMID: 29429832 DOI: 10.1016/j.bmcl.2017.12.068
Abstract

Cyclin-dependent kinases 4/6 play an important role in regulation of cell cycle, and overexpress in a variety of cancers. Up to now, new CDK inhibitors still need to be developed due to its poor selectivity. Herein we report a novel series of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine anologues as potent CDK 4/6 inhibitors based on LY2835219 (Abemaciclib). Compound 10d, which exhibits approximate potency on CDK4/6 (IC50 = 7.4/0.9 nM), has both good pharmacokinetic characters and high selectivity on CDK1 compared with LY2835219. Overall, compound 10d could be a promising candidate and a good starting point as Anticancer drugs.

Keywords

Abemaciclib; Anticancer; CDK1; CDK4/6 inhibitors; Potent; Selective.

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