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.
"Unfortunately, testing of compound 42 in an in vitro model (MDCK cells stably transfected with the gene for the human Pgp transporter), resulted in a high efflux ratio (BA/AB = 97). Therefore, the modification of the P2/P3 amide region did not overcome this challenging problem (Hanessian et al., 2010). "
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Current drug development for the treatment of Alzheimer's Disease is principally based on the amyloid cascade theory, and aims to reduce the levels of Aβ amyloid peptide in the brain. This can be achieved, either by decreasing peptide production through inhibition of β-secretase (also known as BACE-1) or γ-secretase, or by interfering with Aβ aggregation, or by promoting Aβ clearance. Targeting BACE-1, the proteolytic enzyme that initiates Aβ formation, has generated a lot of research interest recently and is currently thought to be one of the most promising therapeutic approaches. In this review, we summarize and discuss the latest patents and publications describing BACE-1 inhibitors, principally focussing on their drug properties and performance in preclinical trials.
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