Cerebrospinal Fluid Amyloid-beta (A beta) as an Effect Biomarker for Brain A beta Lowering Verified by Quantitative Preclinical Analyses

MS#220-4546, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.86). 05/2012; 342(2):366-75. DOI: 10.1124/jpet.112.192625
Source: PubMed

ABSTRACT Reducing the generation of amyloid-β (Aβ) in the brain via inhibition of β-secretase or inhibition/modulation of γ-secretase has been pursued as a potential disease-modifying treatment for Alzheimer's disease. For the discovery and development of β-secretase inhibitors (BACEi), γ-secretase inhibitors (GSI), and γ-secretase modulators (GSM), Aβ in cerebrospinal fluid (CSF) has been presumed to be an effect biomarker for Aβ lowering in the brain. However, this presumption is challenged by the lack of quantitative understanding of the relationship between brain and CSF Aβ lowering. In this study, we strived to elucidate how the intrinsic pharmacokinetic (PK)/pharmacodynamic (PD) relationship for CSF Aβ lowering is related to that for brain Aβ through quantitative modeling of preclinical data for numerous BACEi, GSI, and GSM across multiple species. Our results indicate that the intrinsic PK/PD relationship in CSF is predictive of that in brain, at least in the postulated pharmacologically relevant range, with excellent consistency across mechanisms and species. As such, the validity of CSF Aβ as an effect biomarker for brain Aβ lowering is confirmed preclinically. Meanwhile, we have been able to reproduce the dose-dependent separation between brain and CSF effect profiles using simulations. We further discuss the implications of our findings to drug discovery and development with regard to preclinical PK/PD characterization and clinical prediction of Aβ lowering in the brain.

Download full-text


Available from: Douglas S Johnson, Jul 02, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Drug discovery can benefit from a proactive-knowledge-attainment philosophy which strategically integrates experimentation and pharmacokinetic/pharmacodynamic (PK/PD) modeling. Our programs for Alzheimer's disease (AD) illustrate such an approach. Compounds that inhibit the generation of brain beta amyloid (Aβ), especially Aβ42, are being pursued as potential disease-modifying therapeutics. Complexities in the PK/Aβ relationship for these compounds have been observed and the data require an advanced approach for analysis. We established a semimechanistic PK/PD model that can describe the PK/Aβ data by accounting for Aβ generation and clearance. The modeling characterizes the in vivo PD (i.e., Aβ lowering) properties of compounds and generates insights about the salient biological systems. The learning from the modeling enables us to establish a framework for predicting in vivo Aβ lowering from in vitro parameters.
    Frontiers in Pharmacology 10/2012; 3:177. DOI:10.3389/fphar.2012.00177
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sequential proteolytic cleavage of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex produces the amyloid-β peptide (Aβ), which is believed to play a critical role in the pathology of Alzheimer's disease (AD). The aspartyl protease BACE1 catalyzes the rate-limiting step in the production of 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. The active site of BACE1 is relatively large. Consequently, to achieve sufficient potency, many BACE1 inhibitors have required unfavorable physicochemical properties such as high molecular weight and polar surface area that are detrimental to efficient passage across the blood-brain barrier. Using a rational drug design approach we have designed and developed a new series of hydroxyethylamine-based inhibitors of BACE1 capable of lowering Aβ levels in the brains of rats after oral administration. Herein we describe the in vitro and in vivo characterization of two of these molecules and 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 the chemical series. We demonstrate that high in vitro potency for BACE1 was not sufficient to provide central efficacy. 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.
    Journal of Pharmacology and Experimental Therapeutics 08/2012; 343(2):460-7. DOI:10.1124/jpet.112.197954 · 3.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Beta-site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid beta peptide (Aβ) species. Since cerebral deposition of Aβ species might be critical for the pathogenesis of Alzheimers disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical FRET assay, Aβ and sAPPβ release from modified and wild type human SH-SY5Y cells, mouse N2A cells, as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and Cathepsin D were 14 and >1000 fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain and CSF Aβ levels in mouse, guinea pig and non-human primate. Pharmacokinetic/ Pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduce the levels of Aβ in brain, CSF and plasma in several preclinical species. It might therefore have disease-modifying potential in the treatment of Alzheimers disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.
    Journal of Biological Chemistry 10/2012; DOI:10.1074/jbc.M112.409110 · 4.60 Impact Factor