The amyloid β (Aβ) peptide is believed to play a critical role in the pathology of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) catalyzes the rate-limiting step in the production of the peptide Aβ, and as such it is considered to be an important target for drug development in AD. The development of a BACE1-inhibitor therapeutic has proven to be difficult because many BACE1 inhibitors have unfavorable physicochemical properties, such as high molecular weight and polar surface area, that are detrimental to efficient passage across the blood-brain barrier. This article describes a rational drug design approach for developing a new series of BACE1 inhibitors capable of lowering Aβ levels in the brains of rats after oral administration. The in vitro and in vivo characterization of two compounds is described as well as the overall relationship of compound properties [e.g., in vitro permeability, P-glycoprotein (P-gp) efflux, metabolic stability and pharmacological potency] to the in vivo pharmacodynamic effect with more than 100 compounds across a chemical series. The results demonstrate that a combination of potency, high permeability, low P-gp-mediated efflux, and low clearance was required for compounds to produce robust central Aβ reduction after oral dosing.
See article at J Pharmacol Exp Ther 2012, 343:460–467.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics