Structure-based design and synthesis of novel P2/P3 modified, non-peptidic beta-secretase (BACE-1) inhibitors
ABSTRACT Starting from peptidomimetic BACE-1 inhibitors, the P2 amino acid including the P2/P3 peptide bond was replaced by a rigid 3-aminomethyl cyclohexane carboxylic acid. Co-crystallization revealed an unexpected binding mode with the P3/P4 amide bond placed into the S3 pocket resulting in a new hydrogen bond interaction pattern. Further optimization based on this structure resulted in highly potent BACE-1 inhibitors with selectivity over BACE-2 and cathepsin D.
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ABSTRACT: β-Secretase (memapsin 2; BACE-1) is the first protease in the processing of amyloid precursor protein leading to the production of amyloid-β (Aβ) in the brain. It is believed that high levels of brain Aβ are responsible for the pathogenesis of Alzheimer's disease (AD). Therefore, β-secretase is a major therapeutic target for the development of inhibitor drugs. During the past decade, steady progress has been made in the evolution of β-secretase inhibitors toward better drug properties. Recent inhibitors are potent, selective and have been shown to penetrate the blood-brain barrier to inhibit Aβ levels in the brains of experimental animals. Moreover, continuous administration of a β-secretase inhibitor was shown to rescue age-related cognitive decline in transgenic AD mice. A small number of β-secretase inhibitors have also entered early phase clinical trials. These developments offer some optimism for the clinical development of a disease-modifying drug for AD.Journal of Neurochemistry 11/2011; 120 Suppl 1:71-83. DOI:10.1111/j.1471-4159.2011.07476.x · 4.24 Impact Factor
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ABSTRACT: The asymmetric synthesis of a carbocyclic delta-amino acid representing the P(2)/P(3) subunit of a nonpeptidic truncated peptidomimetic molecule is described relying on two independent approaches.The Journal of Organic Chemistry 04/2010; 75(9):2861-76. DOI:10.1021/jo100017t · 4.64 Impact Factor
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ABSTRACT: β-Secretase 1 (BACE1) is the enzyme involved in the abnormal production of the amyloidogenic peptide Aβ42, one of the major causes of histological hallmarks of Alzheimer's disease. Thus, BACE1 represents a key target protein in the development of new potential drugs for the non-symptomatic treatment of Alzheimer's disease. Since the discovery of BACE1 one decade ago, both in the pharmaceutical industry and in academia there has been an intense search for novel inhibitors to be developed as new effective drugs. There is a great deal of interest in the discovery of selective non-peptide BACE1 inhibitors with a new chemical skeleton, suited for central nervous system penetration and endowed with more appropriate pharmacokinetic properties. Therefore, the selection of appropriate methods for screening and characterization of BACE1 inhibitors is crucial. This review focuses on the description of the in vitro methods to test BACE1 activity and inhibition, with particular emphasis on fluorescence resonance energy transfer (FRET) methods, aiming at critically highlighting advantages and drawbacks. An overview of BACE1 inhibitors is given, underlying the variability of the FRET methods reported in the literature, and the structure evolution of inhibitors active in cellular cultures and in vivo, from peptide to small synthetic and natural structures.Analytical and Bioanalytical Chemistry 06/2011; 400(7):1979-96. DOI:10.1007/s00216-011-4963-x · 3.58 Impact Factor