BIIB042, a novel γ-secretase modulator, reduces amyloidogenic Aß isoforms in primates and rodents and plaque pathology in a mouse model of Alzheimer's disease.

Reducing the production of larger aggregation-prone amyloid ß-peptides (Aß) remains an untested therapeutic approach for reducing the appearance and growth of Aß plaques in the brain, which are a hallmark pathological feature of Alzheimer's disease. γ-Secretase modulators (GSMs) are therapeutics that impact γ-secretase-dependent cleavage of amyloid precursor protein to promote the production of shorter Aß peptides that are less prone to aggregation and plaque deposition. This is accomplished without inhibiting overall γ-secretase function and cleavage of other substrates, which is believed to be a source of deleterious side effects. Here, we report the pharmacokinetic and pharmacodynamic properties of BIIB042, a novel bioavailable and brain-penetrant GSM. In cell-based assays, BIIB042 reduced the levels of Aß42, increased the levels of Aß38 and had little effect on the levels of Aß40, the most abundant Aß species. Similar pharmacodynamic properties were confirmed in the central nervous system and in plasma of mice and rats, and also in plasma of cynomolgus monkeys after a single oral dose of BIIB042. BIIB042 reduced Aß42 levels and Aß plaque burden in Tg2576 mice, which overexpress human amyloid precursor protein and serve as a model system for Alzheimer's disease. BIIB042 did not inhibit cleavage of other γ-secretase substrates in cell-based and in vivo signaling and cleavage assays. The pharmacodynamic effects of lowering Aß42 in the central nervous system coupled with demonstrated efficacy in reducing plaque pathology suggests modulation of γ-secretase, with molecules like BIIB042, is a compelling therapeutic approach for the treatment of Alzheimer's disease.

Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads.

We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer's disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100x more potent than 1, such as 7 (5 nM K(i)).

In vivo neurochemical correlates of cognitive processes: methodological and conceptual challenges.

The advent of the use of in vivo microdialysis and voltammetry techniques in behaving animals has ushered in a great deal of research on the neurochemistry of cognition. While studies exploring the relationship between neurotransmitter release and cognitive processing are quite feasible, a number of methodological and conceptual issues pose challenges to the interpretation of experimental results. These challenges include: 1) a demonstration that the behavioral task highlights the particular cognitive construct under study; 2) a determination of the role of non-cognitive variables (i.e. transfer effects, sensory stimulation, motivational variables, and motor activity) in affecting transmitter release, and 3) a recognition of the value of a distributed systems approach to studying the neurochemistry of cognition. This review summarizes the data on the validity of microdialysis and voltammetry as correlates of neurotransmitter release and then illustrates the impact that the above challenges can have on the conclusions drawn from various studies.