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.
Amino-2H-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 (S)-1m 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 (S)-1m, 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.
The use of non-polar, small polymers as matrices for the analysis of low molecular weight compounds in polymer-assisted laser desorption/ionization mass spectrometry (PALDI-MS) is demonstrated. The matrices evaluated were either based on an oligothiophene or a benzodioxin backbone. Metallocenes, polycyclic hydrocarbons, a fluorosurfactant, and a subset of small organic compounds with various functionalities, served as model analytes. The mechanism of ionization charge transfer is discussed and ionization potentials for the matrices in the study have been estimated using density functional theory (DFT) calculations. Some of the results are possibly contradictory to the generally accepted limiting conditions for gas-phase charge-transfer reactions. These results are interpreted in the light of energy pooling. Also a new mass calibration procedure for the low-mass region in positive ion mode is presented, and some aspects of the ionization/desorption process leading to radical cations are studied.
Thin films of aligned supramolecular architectures built from newly synthesized thiophene-substituted porphyrins have been processed from solution on surfaces.
A cost-efficient and facile synthesis of (S)-4-vinyldihydrofuran-2(3H)-one ((S)-1), better known as (S)-Taniguchi lactone, is described. Racemic Taniguchi lactone rac-1 was ring-opened with (S)-1-benzylmethylamine providing a diastereomeric mixture of hydroxyl-amides. The desired diastereomer (S,S)-2 was isolated by crystallization and subjected to acidic hydrolysis to release enantiopure title compound in good overall yield with an er in excess of 99%. The process was successfully scaled up to kilogram quantities.
A correct determination of the ionization potential (IP) and electron affinity (EA) as wells as the energy gap is essential to properly characterize a series of key phenomena related to...
Small-molecules (SM) have attracted a great deal of attention in the field of solar energy conversion due to their unique properties compared to polymers, such as well-defined molecular weights and lack of regio-isomeric impurities. Furthermore, these materials can be synthesized in a variety of configurational architectures, representing an opportunity for tailoring chemical and optical properties that could lead to a better photocatalytic efficiency for hydrogen generation. Here, we evaluate, by means of density functional theory (DFT) and time-dependent DFT methods, a set of smallmolecules with A-D-A architecture (A, acceptor; D, donor) based on well-known building blocks like thiophene (T), cyclopentadithiophene (CPT), and benzothiadiazole (BT) as potential candidates for photocatalytic hydrogen evolution reaction (HER). We also propose (i) the replacement of the thiophene unit by 3,4ethylenedioxythiophene (EDOT) to form with a CPT unit an extended donor core, (ii) an additional acceptor unit, the 1,3,4-thiadiazole (Tz), in the extremities, and (iii) insertion of the difluoromethoxy (DFM) as a substituent in the BT unit. Our outcomes reveal that these materials have a broad absorption spectrum with λ = 318 to 719 nm being the most intense absorption peak originated from an electronic transition with charge-transfer nature, as the spatial distribution of LUMO is concentrated on the acceptor units for all materials. Moreover, these small-molecules not only present catalytic power or thermodynamic driving force to carry out the chemical reactions involved in the process of hydrogen production but also can be coupled in cooperative photocatalytic systems to promote intramolecular charge transfer that is expected to boost the overall photocatalytic efficiency of these materials.
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