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 |
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| Authors: | 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 |
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| Affiliation: | 1. Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry and Chemical Engineering, Beijing University of Technology, Beijing 100124, PR China;2. Gan&lee Pharmaceuticals R&D, No.8 Jingsheng North 3rd Street, Majuqiao Town, Tongzhou, Beijing 101102, PR China;3. Beijing Handian Pharmaceutical Co. Ltd., Kuntai International Building, Chaoyang, Beijing 100020, PR China |
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| 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. |
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| Keywords: | CDK4/6 inhibitors CDK1 Abemaciclib Potent Selective Anticancer |
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