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Potential novel targets for A lzheimer pharmacotherapy: II . Update on secretase inhibitors and related approaches
Author(s) -
Mikulca J. A.,
Nguyen V.,
Gajdosik D. A.,
Teklu S. G.,
Giunta E. A.,
Lessa E. A.,
Tran C. H.,
Terak E. C.,
Raffa R. B.
Publication year - 2014
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/jcpt.12112
Subject(s) - clinical trial , disease , amyloid precursor protein secretase , medicine , pharmacotherapy , amyloid (mycology) , amyloid precursor protein , pharmacology , alzheimer's disease , bioinformatics , pathology , biology
Summary What is known and objective The prevailing theory regarding A lzheimer disease ( AD ) is that insoluble amyloid β‐peptide ( A β) plays a critical role in the cortical plaques characteristic of the disease. Because A β is formed from the sequential splicing of amyloid precursor protein ( APP ) catalysed by ‘secretase’ enzymes (α, β and γ), clinical trials of secretase inhibitors will either result in beneficial pharmacotherapy or, if negative, cast doubt on the role of A β in AD . With recent clinical trial failures, is the A β theory wrong? Methods Literature searches were conducted on the topics of secretases and clinical trials, including P ub M ed searches, United States clinical trials directory, pharmaceutical company websites and news reports. The information was collected and evaluated for relevance and quality. Results and discussion Several direct‐acting (e.g. CTS ‐21166, LY 2811376) and indirect‐acting (e.g. ACI ‐91) β‐secretase inhibitors and several γ‐secretase inhibitors ( e.g . avagacestat, JNJ ‐40418677 and semagacestat) have not fared well in early clinical trials due to the lack of efficacy or concerns over possible serious side effects. What is new and conclusion The failures of secretase inhibitors in clinical trials appear to bring into question the long‐hypothesized association between AD and A β production. However, the disease might have been too advanced in these patients to benefit from this type of therapy (mainly preventive). Secretase inhibitors are still being studied, along with new diagnostic tools, with the hope of testing patients earlier, that is, with less advanced disease. If these trials also fail, the prevailing view of the role of A β in AD will truly be in doubt.