Search

We report the metal-organic chemical vapor deposition growth of high-quality AlN on sapphire enabled by an alternating V/III ratio AlN superlattice. We demonstrated that the insertion of an alternating V/III ratio AlN superlattice facilitates the relaxation of tensile stress during growth and assists the annihilation of threading dislocations. Dislocation inclination was proposed to play a major role in the stress relaxation and dislocation reduction, which not only provides an effective misfit-dislocation component but also increases the dislocation reaction probability. By this method, crack-free 3.25 μm-thick AlN films were grown on flat sapphire substrate (FSS) and nano-patterned sapphire substrate (NPSS) at 1180 °C, and the full width at half maximum of (002)/(102) rocking curves was 204/408 and 152/323 arcsec for such AlN/FSS and AlN/NPSS templates. [ABSTRACT FROM AUTHOR]

InGaN-based long-wavelength light-emitting diodes (LEDs) are indispensable components for the next-generation solid-state lighting industry. In this work, we introduce additional InGaN/GaN pre-wells in LED structure and investigate the influence on optoelectronic properties of yellow (~575 nm) LEDs. It is found that yellow LED with pre-wells exhibits a smaller blue shift, and a 2.2-fold increase in light output power and stronger photoluminescence (PL) intensity compared to yellow LED without pre-wells. The underlying mechanism is revealed by using Raman spectra, temperature-dependent PL, and X-ray diffraction. Benefiting from the pre-well structure, in-plane compressive stress is reduced, which effectively suppresses the quantum confined stark effect. Furthermore, the increased quantum efficiency is also related to deeper localized states with reduced non-radiative centers forming in multiple quantum wells grown on pre-wells. Our work demonstrates a comprehensive understanding of a pre-well structure for obtaining efficient LEDs towards long wavelengths. [ABSTRACT FROM AUTHOR]

Abstract: SAR of a novel series of pyridine-derived γ-secretase modulators is described. Compound 5 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42 and Aβ40, and maintain (or increase) the levels of total Aβ. Furthermore, representative compounds 1 and 5 demonstrated in vivo efficacy to lower Aβ42 in the brain without altering Notch processing in the peripheral. [Copyright &y& Elsevier]

Abstract: SAR of a novel series of pyridazine-derived γ-secretase modulators is described. Compound 25 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42 and Aβ40, and maintain the levels of total Aβ. Furthermore, 25 demonstrated excellent pharmacokinetic parameters as well as good CNS penetration in the rat. [Copyright &y& Elsevier]

The design, synthesis and SAR of a series of 2,6,9-trisubstituted purine inhibitors of p38α kinase is reported. Synthetic routes were devised to allow for array synthesis in which all three points of diversity could be facilely explored. The binding of this novel series to p38α kinase, which was predicted to have several key interactions in common with SB-203580, was confirmed by X-ray crystallography of 19 (p38 IC50=82 nM). [Copyright &y& Elsevier]

Examines the photodeoxygenation of dibenzothiophene sulfoxide. Evidence for a unimolecular sulfur-oxygen cleavage mechanism; Measurements of quantum yields as a function of concentration, solvent, quenchers and excitation wavelength; Indications that the active oxidizing agent may be atomic oxygen or a closely related noncovalent complex.

Abstract: Design and syntheses of a novel series of muscarinic antagonists are reported. These efforts have culminated in the discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide (4a) as a potent and pan-active muscarinic antagonist as well as a functionally active compound in a murine model of bronchoconstriction. The compound has also displayed pharmacokinetic characteristics suitable for inhaled delivery. [Copyright &y& Elsevier]

Abstract: Chemoselectivity of chlorine versus methylthio (–SCH3), methylsulfinyl (–SOCH3), or methylsulfonyl [–S(O)2CH3] in either functionalization or substitution of pyridopyrimidinone and pyrimidopyrimidinone was studied. Utilization to prepare final targets for accelerated SAR studies via two-dimensional array syntheses has been demonstrated in both systems. [Copyright &y& Elsevier]

Reports the efficient oxenoid functionalization of hydrocarbons which takes place as a result of photolysis of certain aromatic sulfoxides, notably dibenzothiophene sulfoxide. Oxidation products; Competitive oxidation of several substrates.

Graphical abstract Abstract We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23 , which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5 mg/kg/h. [ABSTRACT FROM AUTHOR]

Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson’s disease. Herein we disclose the discovery of a 4-ethoxy-7 H -pyrrolo[2,3- d ]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7 , which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100 mg/kg) and mice (45 mg/kg) following oral administration. [ABSTRACT FROM AUTHOR]

Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson’s disease. Herein we report the discovery of 5-substituent- N -arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e , which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability. [ABSTRACT FROM AUTHOR]

An improved synthesis of trimethylsilyl chlorodifluoroacetate (TCDA) is developed and the reagent is successfully used to introduce CF3-groups into aryl and hetaryl iodides. [ABSTRACT FROM AUTHOR]

Diversely substituted aryl iodides are transformed into the corresponding trifluoromethylated derivatives in varying yields. [ABSTRACT FROM AUTHOR]

Molecules labelled with the unnatural isotope fluorine-18 are used for positron emission tomography. Currently, this molecular imaging technology is not exploited at its full potential because many 18F-labelled probes are inaccessible or notoriously difficult to produce. Typical challenges associated with 18F radiochemistry are the short half-life of 18F (<2 h), the use of sub-stoichiometric amounts of 18F, relative to the precursor and other reagents, as well as the limited availability of parent 18F sources of suitable reactivity ([18F]F- and [18F]F2). There is a high-priority demand for general methods allowing access to [18F]CF3-substituted molecules for application in pharmaceutical discovery programmes. We report the development of a process for the late-stage [18F]trifluoromethylation of (hetero)arenes from [18F]fluoride using commercially available reagents and (hetero)aryl iodides. This [18F]CuCF3-based protocol benefits from a large substrate scope and is characterized by its operational simplicity. [ABSTRACT FROM AUTHOR]

Abstract: Accumulation of amyloid β (Aβ) in brain is a pathological hallmark of Alzheimer's disease (AD). Aβ is generated after sequential cleavage of its parental molecule, amyloid precursor protein (APP), by β- and γ-secretases. Inhibition of γ-secretase activity is an effective approach for the reduction of Aβ levels. Since γ-secretase targets many different substrates, selective inhibition of its cleavage of APP is believed to be critical in order to avoid undesirable side effects. γ-Secretase modulator (GSM) shifts the cleavage site on APP and production of amyloidogenic to non-amyloidogenic Aβ fragments. Since GSMs only modulate and do not block cleavage of γ-secretase substrates, they are believed less likely to produce untoward adverse reactions. Here, we report in vivo Aβ-lowering profiles of a pyridazine and a pyridine-derived GSM: GSM-C (Wan et al., 2011a) and GSM-D (Wan et al., 2011b). Both compounds reduced Aβ40 and Aβ42 productions, increased shorter Aβ fragments, and had little effect on Notch signaling (∼100-fold selective). They had excellent oral bioavailability (97.8% for GSM-C, ∼100% for GSM-D) and good brain permeability (free brain to free blood AUC ratio of 0.41 and 1.10 for GSM-C and GSM-D, respectively). Oral administration of these compounds in both acute and sub-chronic conditions reduced Aβ levels in plasma and brain in rats in a dose- and time-dependent manner. Therefore, GSM-C and GSM-D represent two GSMs that are orally bioavailable and brain-permeable. They could serve as excellent tools in the investigation of the role of Aβ peptides in AD pathogenesis. [Copyright &y& Elsevier]

Abstract: A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction. [Copyright &y& Elsevier]

J. Neurochem. (2012) 121, 277-286. Abstract γ-secretase inhibitors (GSIs) have been developed to reduce amyloid-β (Aβ) production for the treatment of Alzheimer's disease by inhibiting the cleavage of amyloid precursor protein (APP). However, cross-inhibitory activity on the processing of Notch can cause adverse reactions. To avoid these undesirable effects, γ-secretase modulators (GSMs) are being developed to selectively reduce toxic Aβ production without perturbing Notch signaling. As it is also known that GSIs can cause a paradoxical increase of plasma Aβ over the baseline after a transient reduction (known as Aβ-rebound), we asked if GSMs would cause a similar rebound and what the potential mechanism might be. Our studies were performed with one GSI (LY-450139) and two chemically distinct GSMs. Although LY-450139 caused Aβ-rebound as expected in rat plasma, the two GSMs did not. Inhibition of APP processing by LY-450139 induced an accumulation of γ-secretase substrates, α- and β-C-terminal fragments of APP, but neither GSM caused such an accumulation. In conclusion, we discover that GSMs, unlike GSIs, do not cause Aβ-rebound, possibly because of the lack of accumulation of β-C-terminal fragments. GSMs may be superior to GSIs in the treatment of Alzheimer's disease not only by sparing Notch signaling but also by avoiding Aβ-rebound. [ABSTRACT FROM AUTHOR]

Abstract: Exploration of multiple regions of a bi-aryl amine template led to the identification of highly potent M3 muscarinic acetylcholine receptor antagonists such as 14 (pA2 =11.0) possessing good sub-type selectivity for M3 over M2. The structure–activity relationships (SAR) and optimization of the bi-aryl amine series are described. [Copyright &y& Elsevier]

A novel and highly convergent synthesis leading to 2‐phenyl‐quinolines has been developed. As demonstrated in the preparation of 6‐fluoro‐3‐(3‐oxo‐piperazin‐1‐ylmethyl)‐2‐phenyl‐quinoline‐4‐carboxylic acid [(S)‐1‐cyclohexyl‐ethyl]‐amide (8), the method provides fascile access to this class of analogues via the common intermediate 7. [ABSTRACT FROM AUTHOR]

Abstract: A novel and efficient route to 4-substituted-pyrido[2,3-d]pyrimidin-7-ones is described resulting in arrays of compounds with biological interest. [Copyright &y& Elsevier]