Novel γ-secretase modulators: a review of patents from 2008 to 2010

The amyloid precursor protein is first cleaved by β-secretase to generate a 99-residue membrane-bound CTF (C99 or β-CTF), which is subsequently cleaved by γ-secretase to generate amyloid β (Aβ) peptides and the APP intracellular domain. The amyloidogenic Aβ42 has attracted considerable attention because it is thought to be the most pathogenic species associated with Alzheimer's disease progression. New classes of compounds, called γ-secretase modulators (GSMs), have been shown to selectively lower Aβ42 production without shutting down key γ-secretase-dependent signaling pathways. This has become an important therapeutic strategy aimed at modulating Aβ production.

The progress on the clinical development of γ-secretase inhibitors is briefly covered in this review, followed by a discussion of the potential differentiating attributes of GSMs. Then, the patent literature covering novel GSMs is reviewed, focusing on patents from 2008 to 2010.

Much progress has been made in the past 2 years on developing GSMs with improved potency for lowering the production of Aβ42. However, many of these chemotypes are in a challenging chemical space and generally possess higher lipophilicity than most CNS drugs. It will be important to gain a better understanding of the specific target(s) that these GSMs interact with in order to facilitate future drug design efforts.