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

Abstract

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, (S)-32 (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 (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC(50) values of 8.6 and 0.16 nM, respectively, and hERG IC(50) 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.

Biotransformation of Two β-Secretase Inhibitors Including Ring Opening and Contraction of a Pyrimidine Ring

“…The two b-secretase inhibitors (S)-25 and AZD3839, belonging to the aminoisoindolseries (Swahn et al, 2012b), were evaluated with regard to their biotransformation in rats and humans. The main focus is on the biotransformation of (S)-25, but AZD3839 is also discussed, because it showed a different metabolic pattern despite its similar structure.…”

“…Recently, the discovery of the aminoisoindoles as b-secretase inhibitors was reported, including an early lead compound (S)-1-pyridin-4-yl-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine [(S)-25] and (S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl) phenyl)-1H-isoindol-3-amine hemifumarate (AZD3839), both potent and selective inhibitor of b-secretase with Ki values in the nanomolar range (Jeppsson et al, 2012;Swahn et al, 2012b). (S)-25 and AZD3839 produced robust efficacy on Ab biomarkers in plasma and CNS in mice, guinea pigs, and monkeys.…”

“…We have focused our efforts on the metabolism of (S)-25 and have used AZD3839 as a comparator. (Tables 1 and 2) were synthesized at the Medicinal Chemistry Department at CNSP iMed Science, AstraZeneca R&D, Södertälje, Sweden, as described previously (Swahn et al, 2012b).…”

“Ligandability” of Drug Targets: Assessment of Chemical Tractability via Experimental and In Silico Approaches

“…The example of β-secretase-1 (BACE1) from our original work illustrates that even a "low" ligandability score does not a priori preclude the possibility of finding exploitable chemical equity that, in this case, did lead to in vivo active compounds from fragment-based approaches combined with scaffold hopping [60]. The example of β-secretase-1 (BACE1) from our original work illustrates that even a "low" ligandability score does not a priori preclude the possibility of finding exploitable chemical equity that, in this case, did lead to in vivo active compounds from fragment-based approaches combined with scaffold hopping [60].…”

Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839

“…is a b-secretase inhibitor with a promising preclinical profile for treatment of Alzheimer's disease (Jeppsson et al, 2012;Swahn et al, 2012). Data from the hERG assay, the guinea pig MAP assay, and QTc interval in dogs collectively predicted a potential risk for QT interval prolongation at exposures close to those expected for clinical efficacy.…”