A group of small molecule with a more promising

A group of small molecule with a more promising therapeutic mechanism are known as γ-secretase modulators (GSMs), which modulate the cleavage activity of γ-secretase (and likely a host of other substrates) and specifically reduce the levels of the fibrillogenic Aβ42 peptide without altering the ε-site cleavage of APP or numerous other γ-secretase substrates, including Notch (Brendel et al., 2015; Imbimbo et al., 2007; Kounnas et al., 2010; Rogers et al., 2012). Since GSMs spare the ε-site processing of Notch, these compounds are considered likely to be safer and better tolerated than GSIs. Previously, we reported the development and characterization of a series of GSMs with promising biological activities (Kounnas et al., 2010). The initial aminothiazole class of compounds displayed high potency for inhibiting the secretion of the Aβ42 peptide, however these compounds also suffered from poor aqueous solubility (Kounnas et al., 2010). Utilizing rational medicinal chemistry design, a class of aminothiazole GSMs was developed with improved physicochemical properties which include increased aqueous solubility and thus were referred to as soluble GSMs (or SGSMs)(Wagner et al., 2014). Importantly, these SGSMs were effective at reducing the levels of Aβ using cell-based models (D'Avanzo et al., 2015; Wagner et al., 2014). Further pharmacokinetic evaluation of this aminothiazole class of SGSMs in mice identified a lead compound, SGSM-36, which showed good Cinacalcet penetration, as well as good clearance, half-life, and volume of distribution (Rynearson et al., 2016). These results collectively support the continued development of this class of compounds as a potential therapy for AD (Rynearson et al., 2016).
Materials and Methods
Results
Discussion Although AD is a genetically complex disease, 225 known familial AD (FAD) mutations in PSEN1 and PSEN2 afford direct evidence for the importance of PS1 and γ-secretase with respect to the disorder. In addition, most of the 51 FAD mutations in APP are also characterized by altered biological activity of γ-secretase directly affecting the type of Aβ species produced. Biochemical studies of these mutations show a common endpoint which is primarily characterized by increases in the levels of Aβ42 and the Aβ (42:40) ratios, driving the aggregation of Aβ into neurotoxic oligomeric assemblies (Bertram and Tanzi, 2008; Tanzi and Bertram, 2005). Therefore, elucidating the physiological and pathophysiological roles of γ-secretase, and its cleavage products, (e.g. Aβ) are key to evaluating the therapeutic potential of this target for the treatment of AD. The strong implication based on the genetics of AD that the constitution of the Aβ fragments is a central cause of AD led to γ-secretase emerging as a prime therapeutic target. Initially, GSI's garnered intense interest based on their ability to reduce the levels of all Aβ species through a broad-based inhibitory mechanism. However, inhibition of the γ-secretase enzyme led to unanticipated consequences; GSI treatment arrested the proteolytic processing of alternative γ-secretase substrates including Notch leading to significant adverse events. Additionally, inhibiting the processing of APP resulted in the accumulation of upstream CTFs, particularly APP-CTFβ, which is responsible for initiating neurodegenerative process and cognitive decline (Lauritzen et al., 2012). The failure of GSIs as a therapy for AD fueled intense scrutiny of γ-secretase as a target and led to various studies in the genetics, biochemistry and pharmacology to determine the biological roles and numerous substrates of the enzyme. Despite the stigma attached to targeting γ-secretase engendered by GSI's, an alternative class of small molecules, known as GSMs, has been developed, which bind to an allosteric site within the enzyme (Uemura et al., 2010, 2009) and modulate the Aβ isoforms produced. Specifically, GSM treatment attenuates the production of the longer, more fibrillogenic Aβ42 peptide in favor of shorter and more soluble species (i.e. Aβ37 and Aβ38). Since GSMs do not interfere with γ-secretase function, these compounds are likely avoiding the adverse events of GSI's. The clear mechanistic differentiation of GSIs and GSMs is paramount to the development of GSMs for the treatment and prevention of AD. To this end, a thorough investigation of the molecular endo-phenotypes using both cell- and animal-based models of AD, comparing a conventional GSI and a SGSM currently under development has been described in the current study.