Design,synthesis and evaluation of 2-amino-imidazol-4-one derivatives as potent β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors |
| |
| Institution: | 1. National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China;2. Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 21006, China;3. Department of Organic Chemistry, China Pharmaceutical University, Nanjing 211198, China;1. 788 Petit Science Center, Department of Chemistry, Centre for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, United States;2. Atlanta Metropolitan State College, 1630 Metropolitan Parkway, Atlanta, GA 30310, United States;1. National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China;2. Department of Pharmacy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, PR China;3. School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China;4. Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, PR China;5. College of Chemistry & Pharmacy, Northwest A&F University, Yangling, PR China;1. School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. Café s/n, 14040-930 Ribeirão Preto, SP, Brazil;2. Centro de Investigaciones Biologicas (CIB-CSIC), Ramiro de Maeztu 9, Madrid 28040, Spain;3. Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, Madrid 28006, Spain;4. Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil;5. Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Avenida Bandeirantes 3900, 14040-900 Ribeirão Preto, SP, Brazil;1. Department of Chemistry, Khozestan Science and Research Branch, Islamic Azad University, Ahvaz, Iran;2. Department of Chemistry, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran;3. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran;1. Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;2. Academy of Scientific & Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;3. PKPD Toxicology & Formulation Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India |
| |
| Abstract: | Inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) to prevent brain β-amyloid (Aβ) peptide’s formation is a potential effective approach to treat Alzheimer’s disease. In this report we described a structure-based optimization of a series of BACE1 inhibitors derived from an iminopyrimidinone scaffold W-41 (IC50 = 7.1 μM) by Wyeth, which had good selectivity and brain permeability but low activity. The results showed that occupying the S3 cavity of BACE1 enzyme could be an effective strategy to increase the biological activity, and five compounds exhibited stronger inhibitory activity and higher liposolubility than W-41, with L-5 was the most potent inhibitor against BACE1 (IC50 = 0.12 μM, logP = 2.49). |
| |
| Keywords: | Alzheimer’s disease BACE1 inhibitors Design and synthesis Iminopyrimidinone scaffold Structure–activity relationship |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
