Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

Abstract

The rapidly aging population desperately requires new therapies for Alzheimer's disease. Despite years of pharmaceutical research, limited clinical success has been realized, with several failed disease modification therapies in recent years. On the basis of compelling genetic evidence, the pharmaceutical industry has put a large emphasis on brain beta amyloid (Aβ) either through its removal via antibodies or by targeting the proteases responsible for its production. In this Perspective, we focus on the development of small molecules that improve the activity of one such protease, gamma secretase, through an allosteric binding site to preferentially increase the concentration of the shorter non-amyloidogenic Aβ species. After a few early failures due to poor drug-like properties, the industry is now on the cusp of delivering gamma secretase modulators for clinical proof-of-mechanism studies that combine potency and efficacy with improved drug-like properties such as lower cLogP, high central nervous system multiparameter optimization scores, and high sp(3) character.

Characterization of FRM-36143 as a new γ-secretase modulator for the potential treatment of familial Alzheimer’s disease

“…These compounds showed no substrate selectivity, which led to undesirable side effects such as skin cancers, weight loss, infections, and even exacerbated memory decline [25, 27, 28]. After the discovery by Weggen et al [31] that a subset of NSAIDs could selectively lower Aβ 42 without affecting the initial cleavage step by GS (ε cleavage), a lot of research was dedicated to finding new generations of compounds that could mediate similar effects [20, 32]. In our quest to discover GSMs that satisfy all known empirical rules of good central nervous system (CNS) drug-like properties [41–43], we synthesized FRM-36143 (Bursavich MG, Harrison BA, Costa DE, Hodgdon HE, Freeman EA, Hrdlicka LA, Kapadnis S, Moffit J, Murphy DA, Patzke H, Tang C, Wen M, Burnett DA, Koenig G, Blain JF.…”

“…It is now well accepted that this increase is not due to an increased production of Aβ 42 but rather to a reduction in the efficiency of GS to process its substrate (for a review see [20]). The genetic evidence supported the amyloid hypothesis of AD [21–23], which has since been refined to suggest that a form of soluble Aβ, rather than the Aβ aggregates found in amyloid plaques, is responsible for neurotoxicity [24].…”

“…Interestingly, these molecules did not prevent the cleavage of Notch and other substrates, thus making them potentially devoid of on-target related side effects. The first generation of GSMs was based on nonsteroidal anti-inflammatory drug (NSAID) derivatives, but further development has since produced molecules with better potency that are more attractive for the treatment of AD [20, 32]. …”

Intramembrane proteases as drug targets

“…Therefore, the physical properties of these compounds still need to be adjusted in order to improve their drug-like properties. Current efforts are focused on analogs with lower hydrophobicity and lower aromatic ring count (higher sp 3 character)-discussed in a recent review by Bursavich et al [98].…”

Current Opinion on the Role of Neurogenesis in the Therapeutic Strategies for Alzheimer Disease, Parkinson Disease, and Ischemic Stroke; Considering Neuronal Voiding Function

“…Therefore, it is believed the production of toxic Aβ42 should be one of the important targets to enhance neurogenesis in AD patients. It is now well accepted that the increase in Aβ42 plaques is due to a reduction in the efficiency of γ-secretase to process its substrate rather than an increased production of Aβ [37,38]. …”