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

Yan Wang; Wen-Jian Liu; Lei Yin; Heng Li; Zhen-Hua Chen; Dian-Xi Zhu; Xiu-Qing Song; Zhen-Zhen Cheng; Peng Song; Zhan Wang; Zhi-Gang Li

doi:10.1016/j.bmcl.2017.12.068

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. Epub 2018 Jan 31.

Authors

Yan Wang¹, Wen-Jian Liu², Lei Yin², Heng Li², Zhen-Hua Chen², Dian-Xi Zhu², Xiu-Qing Song³, Zhen-Zhen Cheng², Peng Song³, Zhan Wang⁴, Zhi-Gang Li⁵

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinases / antagonists & inhibitors*
Cyclin-Dependent Kinases / metabolism
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Molecular Structure
Piperazines / chemical synthesis
Piperazines / chemistry
Piperazines / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship

Substances

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
Antineoplastic Agents
Imidazoles
Piperazines
Protein Kinase Inhibitors
Pyridines
Pyrimidines
Pyrroles
Cyclin-Dependent Kinases