Review: Gamma-secretase modulators

An excellent review titled ‘γ-Secretase Modulators as Potential Disease Modifying Anti-Alzheimer’s Drugs’ has recently published in J.Med.Chem. The review gives some background to the disease and to the generally, although not universally, accepted hypothesis that amyloid plays a key role in the development of Alzheimer’s disease.  It then outlines the small molecule approaches that the pharmaceutical industry have taken in tackling the production of amyloid and highlights the issues associated with inhibitors of β-secretase (i.e. inhibitors occupy a very challenging chemical space) and γ-secretase (i.e. defining a therapeutic index with respect to Notch inhibition) before focussing on the apparent promise of  γ-secretase modulators (compounds that modify the relative proportions of the isoforms produced without changing the rate at which APP is processed).  The review includes a detailed account of the discovery of γ-secretase modulators; possible modes of action; the different chemical classes of γ-secretase modulator (the bulk of the review); ongoing clinical trials; and an informative conclusion which puts the area into perspective.  There has been a lot of progress in this area over the last few years and it’s going to be really interesting to see how it all develops (with both Chiesi and Eisai having compounds in the clinic). Following recent, failed clinical trials with a γ-secretase modulator and a γ-secretase inhibitor the amyloid hypothesis has been called into question to some extent although the compounds tested were arguably less than fit-for-purpose.  The latest generation of γ-secretase modulators should address the failings associated with these earlier compounds in testing the role of γ-secretase and amyloid in the etiology of Alzheimer’s disease.  However, as the authors of this review also point out, the problems of when to best intervene in the progression of the disease, and how to determine such a point of intervention, also remain as pressing issues in determining how to beat Alzheimer’s disease.  There is probably still some way to go in identifying an effective disease-modifying agent but the recent progress made in the amyloid area should at the very least serve to further our understanding of the disease and help to direct future research efforts.

Possible structure of E-2012. Eisai's first clinical phase gamma-secretase modulator.

Note:  Another recent review of the γ-secretase patent literature from 2008-2010 has also recently been published.

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1 Response to Review: Gamma-secretase modulators

  1. Pingback: Structure-based design of BACE inhibitors | MedChemBuzz

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