Design and synthesis of cyclic acylguanidines as BACE1 inhibitors

Jia-Kuo Liu Wei Gu Xiao-Rui Cheng Jun-Ping Cheng Wen-Xia Zhou Ai-Hua Nie

Citation:  Jia-Kuo Liu, Wei Gu, Xiao-Rui Cheng, Jun-Ping Cheng, Wen-Xia Zhou, Ai-Hua Nie. Design and synthesis of cyclic acylguanidines as BACE1 inhibitors[J]. Chinese Chemical Letters, 2015, 26(10): 1327-1330. doi: 10.1016/j.cclet.2015.07.020 shu

Design and synthesis of cyclic acylguanidines as BACE1 inhibitors

    通讯作者: Wen-Xia Zhou,
    Ai-Hua Nie,
  • 基金项目:

    This work was supported by grants from The National Natural Science Foundation of China (No. 81172924)  (No. 81172924)

    Beijing Municipal Natural Science Foundation (No. 7112106). (No. 7112106)

摘要: Based on the lead compound 1 reported in literature, a series of novel BACE1 inhibitors were designed and synthesized, among which compound 11 exhibited a 14-fold improvement in potency over the lead compound 1. This represents a good lead for the discovery of more promising BACE1 inhibitors for the potential treatment of AD.

English

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    1. [1] J.A. Hardy, G.A. Higgins, Alzheimer's disease:the amyloid cascade hypothesis, Science 256(1992) 184-185.[1] J.A. Hardy, G.A. Higgins, Alzheimer's disease:the amyloid cascade hypothesis, Science 256(1992) 184-185.

    2. [2] D.J. Selkoe, Translating cell biology into therapeutic advances in Alzheimer's disease, Nature 399(1999) A23-A31.[2] D.J. Selkoe, Translating cell biology into therapeutic advances in Alzheimer's disease, Nature 399(1999) A23-A31.

    3. [3] Y. Hamada, Y. Kiso, Recent progress in the drug discovery of non-peptidic BACE1 inhibitors, Expert Opin. Drug Discov. 4(2009) 391-416.[3] Y. Hamada, Y. Kiso, Recent progress in the drug discovery of non-peptidic BACE1 inhibitors, Expert Opin. Drug Discov. 4(2009) 391-416.

    4. [4] Z.N. Zhu, Z.Y. Sun, Y.Z. Ye, et al., Discovery of cyclic acylguanidines as highly potent and selective β-site amyloid cleaving enzyme (BACE) inhibitors:Part I-inhibitor design and validation, J. Med. Chem. 53(2010) 951-965.[4] Z.N. Zhu, Z.Y. Sun, Y.Z. Ye, et al., Discovery of cyclic acylguanidines as highly potent and selective β-site amyloid cleaving enzyme (BACE) inhibitors:Part I-inhibitor design and validation, J. Med. Chem. 53(2010) 951-965.

    5. [5] Z.N. Zhu, Iminoheterocycle as a druggable motif:BACE1 inhibitors and beyond, Trends Pharmacol. Sci. 33(2012) 233-240.[5] Z.N. Zhu, Iminoheterocycle as a druggable motif:BACE1 inhibitors and beyond, Trends Pharmacol. Sci. 33(2012) 233-240.

    6. [6] M.S. Wolfe, Secretase targets for Alzheimer's disease:identification and therapeutic potential, J. Med. Chem. 44(2001) 2039-2060.[6] M.S. Wolfe, Secretase targets for Alzheimer's disease:identification and therapeutic potential, J. Med. Chem. 44(2001) 2039-2060.

    7. [7] R. Silvestri, Boom in the development of non-peptidic β-Secretase (BACE1) inhibitors for the treatment of Alzheimer's disease, Med. Res. Rev. 29(2009) 295-338.[7] R. Silvestri, Boom in the development of non-peptidic β-Secretase (BACE1) inhibitors for the treatment of Alzheimer's disease, Med. Res. Rev. 29(2009) 295-338.

    8. [8] D. Oehlrich, H. Prokopcova, H.J.M. Gijsen, The evolution of amidine-based brain penetrant BACE1 inhibitors, Bioorg. Med. Chem. Lett. 24(2014) 2033-2045.[8] D. Oehlrich, H. Prokopcova, H.J.M. Gijsen, The evolution of amidine-based brain penetrant BACE1 inhibitors, Bioorg. Med. Chem. Lett. 24(2014) 2033-2045.

    9. [9] J.D. Scott, A.W. Stamford, E.J. Gilbert, J.N. Cumming, Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use, WO2011044181A1.[9] J.D. Scott, A.W. Stamford, E.J. Gilbert, J.N. Cumming, Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use, WO2011044181A1.

    10. [10] J.N. Cumming, E.M. Smith, L.Y. Wang, et al., Structure based design of iminohydantoin BACE1 inhibitors:identification of an orally available, centrally active BACE1 inhibitor, Bioorg. Med. Chem. Lett. 22(2012) 2444-2449.[10] J.N. Cumming, E.M. Smith, L.Y. Wang, et al., Structure based design of iminohydantoin BACE1 inhibitors:identification of an orally available, centrally active BACE1 inhibitor, Bioorg. Med. Chem. Lett. 22(2012) 2444-2449.

    11. [11] J. Corey-Bloom, R. Anand, J. Veach, A randomized trial evaluating the efficacy and safety of ENA 713(rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease, Int. J. Geriatr. Psychopharmacol. 1(1998) 55-65.[11] J. Corey-Bloom, R. Anand, J. Veach, A randomized trial evaluating the efficacy and safety of ENA 713(rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease, Int. J. Geriatr. Psychopharmacol. 1(1998) 55-65.

    12. [12] S.I. Finkel, Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer's disease, Clin. Therap. 26(2004) 980-990.[12] S.I. Finkel, Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer's disease, Clin. Therap. 26(2004) 980-990.

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  • 发布日期:  2015-07-23
  • 收稿日期:  2015-03-27
  • 网络出版日期:  2015-05-22
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