Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

“…Because our imaging probe can detect soluble Aβs, we conducted NIRF imaging to investigate whether CRANAD-3 can monitor the rapid reduction of soluble Aβs. We first tested the capacity of CRANAD-3 with the well-characterized BACE-1 inhibitor LY2811376, which could lead to a 60% decrease in the soluble Aβs in mouse cortex after a single oral dose (30 mg/kg) (60). As expected, the fluorescence signal of CRANAD-3 from APP/PS1 mice (n = 4) after LY2811376 treatment was 33% lower than the signal from the same mice before treatment (Fig.…”

Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate for the Treatment of Alzheimer Disease

“…In mouse and guinea pig AZD3839 decreased A␤ levels in plasma at lower concentrations compared with the brain even after correction for differences in exposure. This may also have been observed for other ␤-and ␥-secretase inhibitors in different preclinical species (30,62,63) but not all (56,63). The reason for this is not entirely understood.…”

“…Several studies have convincingly demonstrated that reduction of BACE1 activity can alter amyloid burden in mice (23)(24)(25)(26)(27)(28)(29). Recently, emerging data showed that BACE1 inhibitors also were able to lower CSF A␤ levels in humans in Phase I clinical studies (30). Although many research groups have been aiming to find small molecule inhibitors of BACE1, the development of such inhibitors has been challenging (31).…”

Synthesis and Multitarget Biological Profiling of a Novel Family of Rhein Derivatives As Disease-Modifying Anti-Alzheimer Agents

“…Thus, (±)-7e was roughly equipotent to memoquin, 56 about 50-fold more potent than bis(7)-tacrine 62 and other huprine-based hybrids. 40 Very interestingly, the BACE-1 inhibitory activity of (±)-7e seems to be slightly higher than that of the Lilly's BACE-1 inhibitor LY2811376, a very promising anti-Alzheimer drug candidate whose Phase I clinical trials were recently discontinued due to toxicity issues unrelated to BACE-1 inhibition, 59 even though a head-to-head test in the same assay conditions would be required to confirm that point. Thus, the combination of huprine Y and rhein in a new hybrid molecule with a proper linker chain led to a significant enlargement of the activity profile, namely the strong inhibitory activity on BACE-1 that is not present in any of the parent compounds.…”