Citation: Jia-Kuo Liu, Wei Gu, Xiao-Rui Cheng, Jun-Ping Cheng, Ai-Hua Nie, Wen-Xia Zhou. Design and synthesis of 5-cyclopropyl substituted cyclic acylguanidine compounds as BACE1 inhibitors[J]. Chinese Chemical Letters, ;2016, 27(10): 1626-1629. doi: 10.1016/j.cclet.2016.05.002 shu

Design and synthesis of 5-cyclopropyl substituted cyclic acylguanidine compounds as BACE1 inhibitors

Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China

Corresponding author: Ai-Hua Nie, ahnie512@163.com Wen-Xia Zhou, zhouwx@nic.bmi.ac.cn
Received Date: 1 March 2016
Revised Date: 6 April 2016
Accepted Date: 14 April 2016
Available Online: 11 October 2016

Figures(4)

By taking compound 1 as a lead, a series of 5-cyclopropyl substituted cyclic acylguanidine compounds were designed and synthesized as BACE1 inhibitors, compound 4d exhibited 84-fold improved inhibition efficiency than lead compound 1. The diphenyl fragment at the P3 position and the substituents at the second phenyl ring were essential for the compounds to achieve improved inhibition efficiency. This SAR studies provides new insights into the design and synthesis of more promising BACE1 inhibitors for the potential treatment of AD.
- Alzheimer's disease,
- BACE1 inhibitor,
- β-Secretase,
- Drug discovery,
- Cyclic acylguanidine
1. [1]
  J.A. Hardy, G.A. Higgins. Alzheimer's disease:the amyloid cascade hypothesis[J]. Science, 1992,256:184-185. doi: 10.1126/science.1566067
2. [2]
  E. Hubin, N.A.J. van Nuland, K. Broersen. Transient dynamics of Ab contribute to toxicity in Alzheimer's disease[J]. Cell. Mol. Life Sci., 2014,71:3507-3521. doi: 10.1007/s00018-014-1634-z
3. [3]
  E. Karran, M. Mercken, B. De Strooper. The amyloid cascade hypothesis for Alzheimer's disease:an appraisal for the development of therapeutics[J]. Nat. Rev. Drug Discov., 2011,10:698-712. doi: 10.1038/nrd3505
4. [4]
  T. Jonsson, J.K. Atwal, S. Steinberg. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline[J]. Nature, 2012,488:96-99. doi: 10.1038/nature11283
5. [5]
  R. Vassar, D.M. Kovacs, R. Yan. The beta-secretase enzyme BACE in health and Alzheimer's disease:regulation, cell biology, function, and therapeutic potential[J]. J. Neurosci., 2009,29:12787-12794. doi: 10.1523/JNEUROSCI.3657-09.2009
6. [6]
  G. Evin, C. Hince. BACE1 as a therapeutic target in Alzheimer's disease:rationale and current status[J]. Drugs Aging, 2013,30:755-764. doi: 10.1007/s40266-013-0099-3
7. [7]
  A.K. Ghosh, H.L. Osswald. BACE1(β-secretase) inhibitors for the treatment of Alzheimer's disease[J]. Chem. Soc. Rev., 2014,43:6765-6813. doi: 10.1039/C3CS60460H
8. [8]
  Z. Zhu, Z. Sun, Y. Ye. Discovery of cyclic acylguanidines as highly potent and selective b-site amyloid cleaving enzyme (BACE) Inhibitors:Part I; inhibitor design and validation[J]. J. Med. Chem., 2010,53:951-965. doi: 10.1021/jm901408p
9. [9]
  M.S. Malamas, J. Erdei, I. Gunawan. Design and synthesis of 5, 50-disubstituted aminohydantoins as potent and selective human b-secretase (BACE1) inhibitors[J]. J. Med. Chem., 2010,53:1146-1158. doi: 10.1021/jm901414e
10. [10]
  M.S. Malamas, A. Robichaud, J. Erdei. Design and synthesis of aminohydantoins as potent and selective human b-secretase (BACE1) inhibitors with enhanced brain permeability[J]. Bioorg. Med. Chem. Lett., 2010,20:6597-6605. doi: 10.1016/j.bmcl.2010.09.029
11. [11]
  D. Oehlrich, H. Prokopcova, H.J.M. Gijsen. The evolution of amidine-based brain penetrant BACE1 inhibitors[J]. Bioorg. Med. Chem. Lett., 2014,24:2033-2045. doi: 10.1016/j.bmcl.2014.03.025
12. [12]
  R. Vassar. BACE1 inhibitor drugs in clinical trials for Alzheimer's disease[J]. Alzheimers Res. Ther., 2014,6:89-93. doi: 10.1186/s13195-014-0089-7
13. [13]
  J.K. Liu, W. Gu, X.R. Cheng. Design and synthesis of cyclic acylguanidines as BACE1 inhibitors[J]. Chin. Chem. Lett., 2015,26:1327-1330. doi: 10.1016/j.cclet.2015.07.020
14. [14]
  X.R. Cheng, Y. Zhou, W. Gu. The selective BACE1 inhibitor VIa reduces amyloid-b production in cell and mouse models of Alzheimer's disease[J]. J. Alzheimers Dis., 2013,37:823-834.
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沈阳化工大学材料科学与工程学院沈阳 110142