Hannes A. Braun

Inhibitors and Modulators of β- and γ-Secretase

Most gene mutations associated with Alzheimers disease point to the metabolism of amyloid precursor protein as potential cause. The β- and γ-secretases are two executioners of amyloid precursor protein processing resulting in amyloid β. Significant progress has been made in the selective inhibition of both proteases, regardless of structural information for γ-secretase. Several peptidic and non-peptidic leads were identified and first drug candidates are in clinical trials. This review focuses on the developments since 2003.

Ensemble‐Docking Approach on BACE‐1: Pharmacophore Perception and Guidelines for Drug Design

β‐Secretase (BACE‐1), a key enzyme in the etiopathogenesis and progression of Alzheimer Disease, is the focus of medicinal chemistry efforts both in the pharmaceutical industry and in academia. Despite the availability of diverse peptidomimetic BACE‐1 inhibitors, nonpeptidic compounds suitable for oral delivery and transport across the blood brain barrier are in great demand. Herein, a number of active and structurally diverse inhibitors were selected and subjected to an ensemble‐docking process into five BACE‐1 X‐ray structures. The calculated bioactive conformations of these inhibitors allowed us to build an exhaustive pharmacophore model, which captures both the common geometric and electronic features essential for enzyme inhibition. The model is intended to aid the rational design of new BACE‐1 inhibitors. Furthermore, a comparison of BACE/cathepsin D X‐ray structures was made to provide guidelines for the design of BACE‐selective inhibitors.

Drug development and PET-diagnostics for Alzheimer's disease.

The exact cause of Alzheimers disease is still unknown; despite the dramatic progress in understanding. Most gene mutations associated with Alzheimers disease point to the amyloid precursor protein and amyloid beta. The alpha-, beta- and gamma-secretases are the three executioners of amyloid precursor protein processing. Significant progress has been made in the selective inhibition of these proteases, regardless of the availability of structural information. Several peptidic and non-peptidic leads were identified and first drug candidates are in clinical trials. Cholesterol lowering drugs and metal chelators are also in advanced clinical stages as disease modifiers. Successful trials demand either large cohorts or reliable markers for Alzheimers disease. Therefore, several radiomarkers are under investigation to support such clinical trials.

Modulators and Inhibitors of γ- and β-Secretases

Most gene mutations associated with Alzheimer’s disease point to the metabolism of amyloid precursor protein as a potential cause. The β- and γ-secretases are two executioners of amyloid precursor protein processing resulting in amyloid-β. Significant progress has been made in the selective inhibition of both proteases, regardless of structural information for γ-secretase. Several peptidic and nonpeptidic leads were identified for both targets.