AD is an irreversible and
AD is an irreversible and progressive neurodegenerative disease affecting the COG 133 mg which insidiously destroys memory, thinking skills and cognition. Originally described in 1906 by German physician Alois Alzheimer, AD is characterized by the presence of intraneuronal neurofibrillary tangles of hyperphosphorylated microtubule associated protein tau and extraneuronal neuritic plaques primarily composed of amyloid β-42 (Aβ42). A large body of histopathological and genetic evidence implicates that the processing and deposition of Aβ peptides within the brain is the primary driver of AD progression ultimately leading to dementia. The Aβ peptides are formed as the result of sequential proteolytic cleavages of the amyloid precursor protein (APP) by two aspartyl proteases, β-secretase (BACE-1) and γ-secretase, respectively. APP is first cleaved by BACE-1 which yields membrane bound carboxy-terminal fragment-β (CTF-β) known as C99. Further cleavages of the C99 fragment by γ-secretase releases the APP intracellular domain (AICD) and produces extracellular Aβ peptides which vary in length from 37 to 43 amino acids. Directly implicated in the production of Aβ peptides, BACE-1 and γ-secretase represent attractive targets for the development of AD therapies., , Consequentially, small molecule compounds which curtail the formation of all Aβ species by inhibition of either BACE-1 or γ-secretase have been intensely pursued. Potent γ-secretase inhibitors (GSI) such as semagacestat and avagacestat were developed and demonstrated robust reduction of Aβ peptides. Unfortunately, these GSIs also displayed severe side effects and counter efficacy which resulted in accelerated cognitive decline during clinical evaluation, and thus γ-secretase inhibition strategies were abandoned. As an alternative to inhibition, γ-secretase modulation offers an attractive approach with the goal of attenuating the production of the neurotoxic and aggregation prone Aβ42 isoform, the primary component of neuritic plaques, while not affecting endogenous γ-secretase function. Based on the fact that the vast majority of the more than 200 FAD-linked genetic mutations appear to cause a 2-fold increase in the ratio of the longer Aβ42 peptide to the shorter Aβ40 peptide, and a large body of data pointing specifically to Aβ42 in pathogenesis, a therapeutic rationale that modulates γ-secretase activity to reduce the level of Aβ42 relative to the shorter Aβ peptides (i.e., Aβ40, Aβ38 and Aβ37) without affecting overall γ-secretase function may prove to be an efficacious course for interrupting AD progression. Several classes of γ-secretase modulators have been discovered which alter the Aβ cleavage pattern in favor of shorter Aβ peptides, including compounds derived from non-steroidal anti-inflammatory drugs (NSAIDs), aryl imidazoles, and triterpenes. Previously our lab discovered a series of aminothiazole-derived γ-secretase modulators (AGSMs) through rational hit to lead optimization efforts which demonstrate remarkable potency for lowering Aβ42 (>1000-fold more potent than the NSAID-like GSM tarenflurbil) and exhibit moderate brain penetrance. This novel class of compounds is characterized by a tetracyclic scaffold composed of bridged linear aromatics (). Compounds within this series have been shown to specifically reduce the levels of Aβ42 and Aβ40 production while simultaneously increasing the levels of Aβ38 and Aβ37, thereby leaving the total amount of Aβ produced unchanged. Importantly, AGSMs do not affect γ-secretase-mediated cleavage of other critical substrates, including Notch and E-cadherin. The selectivity for Aβ products likely stems from the observed binding of AGSMs to Pen-2 and PS-1 NTF of the γ-secretase enzymatic complex which shifts rather than inhibits endogenous function. Additionally, in vivo studies showed AGSMs were potent and effective at decreasing the levels of Aβ42 and Aβ40 in the plasma and brain of APP transgenic mice. Chronic administration of AGSMs to Tg2576 APP transgenic mice resulted in dramatic reduction of AD-like pathology in the absence of GSI-related effects such as intestinal goblet cell hyperplasia due a distinct mode of action. Despite the overall efficacy of these compounds, the poor aqueous solubility (<0.1μM at neutral pH) of the AGSMs presents a significant liability especially when attempting to achieve the supraefficacious exposures required for safety and toxicology studies during preclinical development.