Beta secretase inhibitor

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Beta secretase inhibitors ( BACE inhibitors ) are potential drugs for a future therapy of Alzheimer's disease . No drug based on this approach is currently approved .

Working principle

The mechanism of action consists in an inhibition (blocking) of the function of beta-secretase (BACE1). The enzyme beta-secretase plays an important role in breaking down the amyloid precursor protein (APP). The beta-amyloid peptide produced by the cleavage leads to the formation of senile plaques , which ultimately lead to Alzheimer's disease.

The idea of developing potential active ingredients against Alzheimer's disease by inhibiting beta-secretase originated in the late 1990s. With the understanding of the molecular processes involved in the development of Alzheimer's disease, beta-secretase was identified as a target .

Status of drug development

Beta secretase inhibitors are still in the early stages of drug development. According to general estimates by experts, a drug against Alzheimer's disease based on a beta-secretase inhibitor will only be available on the market from 2018 at the earliest. The US pharmaceutical company Merck (MSD) is conducting a phase II / III study. The Japanese pharmaceutical company Eisai (developer of donepezil ) also has a BACE inhibitor (E2609) in clinical development.

In July 2019, Amgen and Novartis announced that they had discontinued joint development of the BACE1 inhibitor CNP520 ( umibecestat ).

Other potential candidates for the treatment of Alzheimer's disease are gamma-secretase inhibitors and the active or passive immunization against beta-amyloid known as " Alzheimer's vaccination " .

literature

  • J. Varghese: BACE: Lead Target for Orchestrated Therapy of Alzheimer's Disease , John Wiley & Sons; Edition: 1st edition (March 19, 2010), ISBN 978-0470293423
  • Rajendran L, Schneider A, Schlechtingen G, et al. : Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting . In: Science . 320, No. 5875, April 2008, pp. 520-3. doi : 10.1126 / science.1156609 . PMID 18436784 .
  • Membrane anchor increases the effectiveness of an experimental Alzheimer's drug. In: Deutsches Ärzteblatt from April 25, 2008
  • Lecanu L, Papadopoulos V: Cutting-edge patents in Alzheimer's disease drug discovery: anticipation of potential future treatments . In: Recent Pat CNS Drug Discov . 2, No. 2, June 2007, pp. 113-23. PMID 18221222 .
  • Ghosh AK, Bilcer G, Hong L, Koelsch G, Tang J: Memapsin 2 (beta-secretase) inhibitor drug, between fantasy and reality . In: Curr Alzheimer Res . 4, No. 4, September 2007, pp. 418-22. PMID 17908045 .

Individual evidence

  1. ^ Vassar R, Bennett BD, Babu-Khan S, et al. : Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE . In: Science . 286, No. 5440, October 1999, pp. 735-41. PMID 10531052 .
  2. ↑ Vassar R: Beta-secretase (BACE) as a drug target for Alzheimer's disease . In: Adv Drug Deliv Rev . 54, No. 12, December 2002, pp. 1589-602. PMID 12453676 .
  3. ↑ Evin G, Kenche VB: BACE inhibitors as potential therapeutics for Alzheimer's disease . In: Recent Pat CNS Drug Discov . 2, No. 3, November 2007, pp. 188-99. PMID 18221231 .
  4. ↑ Merck Initiates Phase II / III Study of Investigational BACE Inhibitor, MK-8931, for Treatment of Alzheimer's Disease , Merck press release dated December 3, 2012
  5. ↑ EISAI presents first clinical data for BACE Inhibitor E2609 at Alzheimer's Association International Conference (AAIC) 2012 , Eisai press release from July 19, 2012
  6. ↑ Amgen, Novartis And Banner Alzheimer's Institute Discontinue Clinical Research Program With BACE Inhibitor CNP520 For Alzheimer's Prevention , Amgen PM, July 11, 2019, accessed July 12, 2019
  7. ↑ Evin G, Sernee MF, Masters CL: Inhibition of gamma-secretase as a therapeutic intervention for Alzheimer's disease: prospects, limitations and strategies . In: CNS Drugs . 20, No. 5, 2006, pp. 351-72. PMID 16696577 .