The novel β‐secretase inhibitor KMI‐429 reduces amyloid β peptide production in amyloid precursor protein transgenic and wild‐type mice

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major component of the plaques, amyloid b peptide (Ab), is generated from amyloid precursor protein (APP) by b-and c-secretase-mediated cleavage. Because b-secretase/beta-site APP cleaving enzyme 1 (BACE1) knockout mice produce much less Ab and grow normally, a b-secretase inhibitor is thought to be one of the most attractive targets for the development of therapeutic interventions for AD without apparent side-effects. Here, we report the in vivo inhibitory effects of a novel b-secretase inhibitor, KMI-429, a transition-state mimic, which effectively inhibits b-secretase activity in cultured cells in a dosedependent manner. We injected KMI-429 into the hippocampus of APP transgenic mice. KMI-429 significantly reduced Ab production in vivo in the soluble fraction compared with vehicle, but the level of Ab in the insoluble fraction was unaffected. In contrast, an intrahippocampal injection of KMI-429 in wildtype mice remarkably reduced Ab production in both the soluble and insoluble fractions. Our results indicate that the b-secretase inhibitor KMI-429 is a promising candidate for the treatment of AD. Keywords: Alzheimer's disease, amyloid b peptide, b-secretase inhibitor, beta-site APP cleaving enzyme 1, hydroxymethylcarbonyl isostere, KMI inhibitor. Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose primary pathogenic event is the extracellular accumulation of amyloid b peptide (Ab), followed by oxidative damage to neurons that ultimately results in

First Demonstration of Cerebrospinal Fluid and Plasma Aβ Lowering with Oral Administration of a β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor in Nonhuman Primates

“…The structural requirements for binding also impart high susceptibility to P-glycoprotein (P-gp) transport, thus reducing brain concentrations of BACE-1 inhibitors (Mahar Doan et al, 2002). A few BACE1 inhibitors have been shown to lower brain A␤ levels after direct intracranial administration (Asai et al, 2006;Nishitomi et al, 2006;Sankaranarayanan et al, 2008) or via peripheral administration at relatively high doses in murine models (Chang et al, 2004;Stachel et al, 2006;Hussain et al, 2007;Stanton et al, 2007). However, the lack of potent inhibitors that also possess good pharmacokinetic and brain penetration properties have prevented evaluation of BACE1 inhibitors in larger animals, such as nonhuman primates.…”

Design of Potent Aspartic Protease Inhibitors to Treat Various Diseases

“…Consequently, we designed in a tetrazole moiety, 1H-tetrazole-5-carbonyl, as a bioisostere of the P4-free carboxylic acid of the oxalyl group, and synthesized compound 27 (KMI-429) that exhibited improved stability while maintaining high inhibitory potency. While in-vitro HEK293 cell assays revealed that pentapeptide 27 (KMI-429) dose-dependently inhibited sAPPb production, in-vivo injections of compound 27 into the hippocampus of APP wild type and transgenic Tg2576 mice, respectively, inhibited both amyloid-b production and release of sAPPb in both models [85]. Our docking simulation study showed that KMI-429 was optimized to bind to the active site of BACE1, as shown in Fig.…”

Development of an Efficient Therapeutic Agent for Alzheimer's Disease: Design and Synthesis of Dual Inhibitors of Acetylcholinesterase and Serotonin Transporter

“…Recent progress in the understanding of the pathology of Alzheimer disease has made it possible for potential disease-modifying therapies to be tested in clinical trials. [7][8][9][10][11] However, no such therapy is available at present. Therefore, cholinergic enhancement remains the most effective therapeutic method to treat AD.…”