AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics

• A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-beta peptide (A beta) concentrations, plays a key role in the pathogenesis of Alzheimer's disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-beta protein precursor (A beta PP) to A beta peptides, with the soluble N terminal fragment of A beta PP (sA beta PP beta) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of A beta. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose-and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of A beta(40), A beta(42), and sA beta PP beta. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of A beta. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.

Ämnesord

NATURVETENSKAP  -- Kemi -- Annan kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences -- Other Chemistry Topics (hsv//eng)

Nyckelord

Alzheimer's disease

amyloid-beta

drug therapy

pharmacology

preclinical drug evaluation

neurokemi med molekylär neurobiologi

Neurochemistry with Molecular Neurobiology

Publikations- och innehållstyp

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