A Three-Step Method for the Preparation of N-Substituted 3,4-Dihydroisoquinolin-1(2H)-ones and Heteroaryl-Fused 3,4-Dihydropyridin-2(1H)-ones from 2-Bromobenzoate Precursors.

We demonstrate a general method for the preparation of diverse N-substituted 3,4-dihydroisoquinolin-1(2H)-one compounds through an overall three-step cross-coupling/cyclization/N-deprotection/N-alkylation sequence. In the first step, ethyl 2-bromobenzoates and 2-bromo-1-carboxyethyl heterocycles are cross-coupled with commercially available potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate to produce (hetero)aryl-substituted 3-[(N-Boc-2-carboxyethyl)phenyl]ethylamines. In a subsequent two-stage process, these (hetero)arylethylamines undergo base-mediated ring closure followed by N-deprotection and N-alkylation to produce N-substituted 3,4-dihydroisoquinolin-1(2H)-ones and heteroaryl-fused N-benzyl 3,4-dihydropyridin-2(1H)-ones. Mechanistic work was performed to elucidate the order of transformations for the latter two-stage process. The method was also extended to the production of N-benzyl isoindolin-1-one and N-benzyl 2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one.

Heteroatom Manipulation of Zeolite Crystallization: Stabilizing Zn-FAU against Interzeolite Transformation.

The preparation of metastable zeolites is often restricted to a limited range of synthesis conditions, which is exemplified in commercial syntheses lacking organics to stabilize the crystal structure. In the absence of an organic structure-directing agent, interzeolite transformation is a common phenomenon that can lead to undesirable products or impurities. Many studies have investigated the substitution of Si and Al in zeolite frameworks with alternative elements (heteroatoms) as a means of tailoring the properties of zeolites; however, relatively few studies have systematically explored the impact of heteroatoms on interzeolite transformations and their concomitant effects on zeolite crystallization. In this study, we examine methods to prepare isostructures of faujasite (FAU), which is one of the most commercially relevant zeolites and also a thermodynamically metastable structure. A survey of multivalent elements revealed that zinc is capable of stabilizing FAU at high temperatures and inhibiting its frequent transformation to zeolite gismondine (GIS). Using combined experimental and computational studies, we show that zinc alters the chemical nature of growth mixtures by sequestering silicates. Zinc heteroatoms incorporate in the FAU framework with a loading-dependent coordination. Our collective findings provide an improved understanding of driving forces for the FAU-to-GIS interzeolite transformation where we observe that heteroatoms (e.g., zinc) can stabilize zeolite FAU over a broad range of synthesis conditions. Given the growing interest in heteroatom-substituted zeolites, this approach to preparing zinc-containing FAU may prove applicable to a broader range of zeolite structures.

Design, Synthesis, and Preclinical Efficacy of Novel Nonretinoid Antagonists of Retinol-Binding Protein 4 in the Mouse Model of Hepatic Steatosis.

Retinol-binding protein 4 (RBP4) serves as a transporter for all- trans-retinol (1) in the blood, and it has been proposed to act as an adipokine. Elevated plasma levels of the protein have been linked to diabetes, obesity, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Recently, adipocyte-specific overexpression of RBP4 was reported to cause hepatic steatosis in mice. We previously identified an orally bioavailable RBP4 antagonist that significantly lowered RBP4 serum levels in Abca4-/- knockout mice with concomitant normalization of complement system protein expression and reduction of bisretinoid formation within the retinal pigment epithelium. We describe herein the discovery of novel RBP4 antagonists 48 and 59, which reduce serum RBP4 levels by >80% in mice upon acute oral dosing. Furthermore, 59 demonstrated efficacy in the transgenic adi-hRBP4 murine model of hepatic steatosis, suggesting that RBP4 antagonists may also have therapeutic utility for the treatment of NAFLD.

The relationship between early life stress and working memory in adulthood: A systematic review and meta-analysis.

Exposure to early life stress has been linked to impairment in cognitive functioning in adulthood. The aim of this study was to systematically review the literature on the relationship between early life stress and working memory, a central component of cognitive functioning. Database searches yielded 358 abstracts matching the search terms. Abstract screening followed by full-text review resulted in 26 publications suitable for inclusion, of which 23 were included in the meta-analysis. Results of the meta-analysis suggested exposure to early life stress was associated with poorer working memory. Even though there were a wide variety of working memory tasks used, this effect was significant for both phonological and visuospatial working memory tasks, and both visual and aural task presentation modalities. The effect was also found in samples with and without clinical psychopathology. This review provides recommendations for future research and implications for clinical practice.

A Comparison of Single and Multi-Test Working Memory Assessments in Predicting Academic Achievement in Children.

Children assessed as having low working memory capacity have also been shown to perform more poorly than their same-aged peers in measures of academic achievement. Early detection of working memory problems is, therefore, an important first step in reducing the impact of a working memory deficit on the development of academic skills. In this study, we compared a single-test assessment, the Working Memory Power Test for Children (WMPT) and a multi-test assessment, the Automated Working Memory Assessment (AWMA), in their ability to predict academic achievement in reading, numeracy, and spelling. A total of 132 Australian school children (mean age 9 years, 9 months) participated in the research. Strong positive correlations between the WMPT and AWMA total scores were found, indicating good convergent validity of the single and multi-test measures. WMPT scores correlated with each of the four AWMA subtests designed to assess verbal and visuospatial short-term and working memory. WMPT and AWMA scores separately predicted performance on Word Reading, Numerical Operations, and Spelling. Compared with either measure alone, the WMPT and the AWMA in combination predicted more of the variance in Word Reading and Numerical Operations, but not in Spelling. Theoretical and practical implications of these findings are discussed.

Bicyclic [3.3.0]-Octahydrocyclopenta[c]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease.

Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-trans retinol (1) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is associated with the pathogenesis of both dry age-related macular degeneration (AMD) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant vision loss associated with geographic atrophy of the macula. We previously disclosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo analogue 4. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of 4, which led to the discovery of standout antagonist 33. Analogue 33 possesses exquisite in vitro RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels in vivo in a robust manner (>90%).

Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and Stargardt disease.

Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4(-/-) mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.

5-(pyridinon-1-yl)indazoles and 5-(furopyridinon-5-yl)indazoles as MCH-1 antagonists.

A new series of 5-(pyridinon-1-yl)indazoles with MCH-1 antagonist activity were synthesized. Potential cardiovascular risk for these compounds was assessed based upon their interaction with the hERG potassium channel in a mini-patch clamp assay. Selected compounds were studied in a 5-day diet-induced obese mouse model to evaluate their potential use as weight loss agents. Structural modification of the 5-(pyridinon-1-yl)indazoles to give 5-(furopyridinon-5-yl)indazoles provided compounds with enhanced pharmacokinetic properties and improved efficacy.