Creation of Novel Cores for β‑Secretase (BACE-1) Inhibitors: A Multiparameter Lead Generation Strategy

In order to find optimal core structures as starting points for lead optimization, a multiparameter lead generation workflow was designed with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer’s disease. De novo design of core fragments was connected with three predictive in silico models addressing target affinity, permeability, and hERG activity, in order to guide synthesis. Taking advantage of an additive SAR, the prioritized cores were decorated with a few, well-characterized substituents from known BACE-1 inhibitors in order to allow for core-to-core comparisons. Prediction methods and analyses of how physicochemical properties of the core structures correlate to in vitro data are described. The syntheses and in vitro data of the test compounds are reported in a separate paper by Ginman et al. [<i>J. Med. Chem.</i> <b>2013</b>, <i>56</i>, 4181–4205]. The affinity predictions are described in detail by Roos et al. [<i>J. Chem. Inf.</i> <b>2014</b>, DOI: 10.1021/ci400374z]

Toward β‑Secretase‑1 Inhibitors with Improved Isoform Selectivity

BACE1 is responsible for the first step in APP proteolysis, leading to toxic Aβ production, and has been indicated to play a key role in the pathogenesis of Alzheimer’s disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform-selective BACE1 inhibitors. Cocrystal structures of 47 compounds were analyzed and clustered according to their selectivity profiles. Selective BACE1 inhibitors were found to exhibit two distinct conformational features proximal to the flap and the S3 subpocket. Several new molecules were designed and tested to make use of this observation. The combination of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in lead molecule <b>28</b>, which exhibited ∼50-fold selectivity. Compared to a nonselective BACE1/2 inhibitor, <b>28</b> showed significantly less inhibition of PMEL processing in human melanocytes, indicating good functional selectivity of this inhibitor class

Low estimated glomerular filtration rate is associated with poor outcomes in patients who suffered a large artery atherosclerosis stroke

[[abstract]]Objectives: The relationship between low estimated glomerular filtration rate (eGFR) and the outcome of ischemic stroke remains controversial, despite the close association between kidney dysfunction and atherosclerosis. Methods: This study conducted subgroup analysis using data from the prospective Taiwan Stroke Registry to investigate the relationship between eGFR at the time of admission and 6-month functional outcomes in patients with the large artery atherosclerotic (LAA) subtype of acute ischemic stroke. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS), and outcomes were defined as modified Rankin Scale and mortality status at 6 months post stroke. Results: Of the 8052 patients with the LAA subtype of acute ischemic stroke in this study, 3312 (41.1%) had eGFR 15 and eGFR <15mL/min/1.73m2, compared with those with NIHSS 0-5 and eGFR 60-119mL/min/1.73m2. Conclusions: Low eGFR was significantly and independently associated with 6-month functional outcomes and mortality in patients with the LAA subtype of acute ischemic stroke. The deleterious relationship between low eGFR levels and mortality following stroke was exacerbated by its synergistic association with stroke severity

New Aminoimidazoles as β‑Secretase (BACE-1) Inhibitors Showing Amyloid‑β (Aβ) Lowering in Brain

Amino-2<i>H</i>-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer’s disease. Synthetic methods, crystal structures, and structure–activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (<i>S</i>)-<b>1m</b> was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (<i>S</i>)-<b>1m</b>, a concentration and time dependent decrease in Aβ40 and Aβ42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Aβ was 40–50%, 1.5 h after oral dosing (100 μmol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo

Design and Synthesis of β‑Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors with in Vivo Brain Reduction of β‑Amyloid Peptides

The evaluation of a series of aminoisoindoles as β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer’s disease, (<i>S</i>)-<b>32</b> (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of Aβ40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (<i>S</i>)-<b>16</b> and (<i>R</i>)-<b>41</b> showing large in vitro margins with BACE1 cell IC₅₀ values of 8.6 and 0.16 nM, respectively, and hERG IC₅₀ values of 16 and 2.8 μM, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of β-amyloid peptides in mouse brain following oral dosing