The Structural Evolution of β-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors

Author(s): Stefania Butini, Simone Brogi, Ettore Novellino, Giuseppe Campiani, Arun K. Ghosh, Margherita Brindisi, Sandra Gemma.

Journal Name: Current Topics in Medicinal Chemistry

Volume 13 , Issue 15 , 2013

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Effective treatment of Alzheimer’s disease (AD) remains a critical unmet need in medicine. The lack of useful treatment for AD led to an intense search for novel therapies based on the amyloid hypothesis, which states that amyloid β-42 (Aβ42) plays an early and crucial role in all cases of AD. β-Secretase (also known as BACE-1 β-site APP-cleaving enzyme, Asp-2 or memapsin-2) is an aspartyl protease representing the rate limiting step in the generation of Aβ peptide fragments, therefore it could represent an important target in the steady hunt for a disease-modifying treatment. Generally, β-secretase inhibitors are grouped into two families: peptidomimetic and nonpeptidomimetic inhibitors. However, irrespective of the class, serious challenges with respect to blood–brain barrier (BBB) penetration and selectivity still remain. Discovering a small molecule inhibitor of β-secretase represents an unnerving challenge but, due to its significant potential as a therapeutic target, growing efforts in this task are evident from both academic and industrial laboratories. In this frame, the rising availability of crystal structures of β-secretase-inhibitor complexes represents an invaluable opportunity for optimization. Nevertheless, beyond the inhibitory activity, the major issue of the current research approaches is about problems associated with BBB penetration and pharmacokinetic properties. This review follows the structural evolution of the early β-secretase inhibitors and gives a snap-shot of the hottest chemical templates in the literature of the last five years, showing research progress in this field.

Keywords: Alzheimer’s disease, BACE-1, β-secretase, peptidomimetic inhibitors, protease inhibitors, small-molecule inhibitors.

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Article Details

Year: 2013
Page: [1787 - 1807]
Pages: 21
DOI: 10.2174/15680266113139990137
Price: $58

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