Discovery of a novel series of GPR119 agonists: Design, synthesis, and biological evaluation of N-(Piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives.

We undertook an optimization effort involving propan-2-yl 4-({6-[5-(methanesulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate 1, which we had previously discovered as a novel G protein-coupled receptor 119 (GPR119) agonist. To occupy a presumed hydrophobic space between the pyrimidine and piperidine rings in interaction with GPR119, we replaced the linker oxygen with nitrogen. Subsequently, the introduction of a substituent at the bridging nitrogen atom was explored. We found that the installation of N-trifluoromethyl group 10 not only enhanced GPR119 agonist activity but also considerably improved the human ether-à-go-go-related gene (hERG) inhibition profile. These improvements were not observed for non-fluorinated substituents, such as ethyl analog 8b. The next optimization effort focused on the exploration of a new surrogate structure for the indoline ring and the isosteric replacements of the piperidine N-Boc group to improve solubility, metabolic stability, and oral bioavailability. As a result, N-{1-[3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}-6-{[1-(methanesulfonyl)piperidin-4-yl]oxy}-N-(trifluoromethyl)pyrimidin-4-amine (27) was identified as a potent and orally bioavailable GPR119 agonist. This compound augmented insulin secretion and effectively lowered plasma glucose excursion in a diabetic animal model after oral administration. In this study, we discuss the designs, syntheses, and biological activities of a novel series of N-(piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives as GPR119 agonists, and to determine the distinctive effect of the N-trifluoromethyl group on hERG inhibition, we also discuss the conformational preference of representative compounds.

Visible-Light-Activated Response Originating from Carrier-Mobility Modulation of NO2 Gas Sensors Based on MoS2 Monolayers.

Some gas sensors exhibit significant increases in their sensitivity and response/recovery rates under light illumination. This photoactivation of the gas response is considered a promising alternative to conventional thermal activation, which requires high power consumption. Thin layers of molybdenum disulfide (MoS2) are known to exhibit an effective photoactivated gas response under visible light. However, the mechanism of the photoactivated response has not yet been studied in detail. In this study, we fabricated field-effect-transistor (FET) gas sensors based on MoS2 monolayers and investigated their photoactivated gas responses to NO2 gas under illumination at various irradiances of visible light. A photocurrent was generated mainly due to the photovoltaic effect, which decreased upon exposure to NO2. The conductance-based sensor response showed a dependence on NO2 concentration according to the Langmuir adsorption isotherm, thereby suggesting that the response is proportional to the surface coverage of NO2 molecules on the MoS2 layer. The response and recovery rates showed a linear increase with increasing irradiance. Analysis based on the Langmuir adsorption model revealed that both photostimulated adsorption and desorption are involved in the photoactivated response. In contrast, despite the strong dependence of the photocurrent on the irradiance, the magnitude of the sensor response was independent of the irradiance. Based on this result and the change in transfer characteristics of the FET during NO2 exposure, we concluded that the fast response/recovery of the photoactivated response is due to the carrier mobility modulation of MoS2, which is caused by the dipole scattering of adsorbed NO2 molecules.

Discovery of a novel series of indolinylpyrimidine-based GPR119 agonists: Elimination of ether-a-go-go-related gene liability using a hydrogen bond acceptor-focused approach.

We previously identified a novel series of indolinylpyrimidine derivatives exemplified by 2 in Figure 1, which is an indoline based derivative, as potent GPR119 agonists. Despite the attractive potency of 2, this compound inhibited the human ether-a-go-go-related gene (hERG) K+ channel. We elucidated crucial roles of the methylsulfonyl group of 2 in its interaction with the hERG channel and the GPR119 receptor, presumably as a hydrogen bond acceptor (HBA). To remove the undesirable hERG inhibitory activity, a strategy was implemented to arrange an HBA on a less conformationally flexible framework at the indoline 5-position instead of the methylsulfonyl group. This successfully led to the discovery of a piperidinone ring as a desirable motif at the indoline 5-position, which could minimize hERG liability as shown by 24b. Further optimization focused on the reduction of lipophilicity in terms of more favorable drug-like properties. Consequently, the introduction of a hydroxy group at the 3-position of the piperidinone ring effectively reduced lipophilicity without compromising GPR119 potency, resulting in the identification of (3S)-3-hydroxy-1-{1-[6-({1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}oxy)pyrimidin-4-yl]- 2,3-dihydro-1H-indol-5-yl}piperidin-2-one ((S)-29) as a novel, potent, and orally bioavailable GPR119 agonist with a well-balanced profile. The pharmacological effects of this compound were also confirmed after single and chronic oral administration in diabetic animal models.

Bias- and Gate-Tunable Gas Sensor Response Originating from Modulation in the Schottky Barrier Height of a Graphene/MoS2 van der Waals Heterojunction.

We report on the gas-sensing characteristics of a van der Waals heterojunction consisting of graphene and a MoS2 flake. To extract the response actually originating from the heterojunction area, the other gas-sensitive parts were passivated by gas barrier layers. The graphene/MoS2 heterojunction device demonstrated a significant change in resistance, by a factor of greater than 103, upon exposure to 1 ppm NO2 under a reverse-bias condition, which was revealed to be a direct reflection of the modulation of the Schottky barrier height at the graphene/MoS2 interface. The magnitude of the response demonstrated strong dependences on the bias and back-gate voltages. The response further increased with increasing reverse bias. Conversely, it dramatically decreased when measured at a large forward bias or a large positive back-gate voltage. These behaviors were analyzed using a metal-semiconductor-metal diode model consisting of graphene/MoS2 and counter Ti/MoS2 Schottky diodes.

Optimization of a novel series of N-phenylindoline-5-sulfonamide-based acyl CoA:monoacylglycerol acyltransferase-2 inhibitors: Mitigation of CYP3A4 time-dependent inhibition and phototoxic liabilities.

Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has emerged as a potential peripheral target for the treatment of obesity and metabolic disorders. We previously identified a novel series of N-phenylindoline-5-sulfonamide derivatives exemplified by 2 as potent and orally bioavailable MGAT2 inhibitors. Despite its attractive potency, further assessment revealed that this compound exhibited time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4). To remove the undesirable CYP3A4 TDI activity, structural modification was focused on the 2,4-difluoroaniline moiety on the basis of the assumption that this moiety would be involved in mechanism-based inhibition of CYP3A4 via oxidative metabolism. This led to the finding that the introduction of 4-chloro-2,6-difluoroaniline significantly improved CYP3A4 TDI risk. Further optimization resulted in the discovery of N-(4-chloro-2,6-difluorophenyl)-1-{5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]pyrimidin-2-yl}-7-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-indole-5-sulfonamide (27c) with potent MGAT2 inhibitory activity (IC50=7.8 nM) and excellent ADME-Tox profiles including metabolic stability, oral bioavailability, and CYP3A4 TDI. In a mouse oral fat tolerance test, compound 27c effectively and dose-dependently suppressed the elevation of plasma triacylglycerol levels after oral administration at doses of 1 and 3mg/kg. We also discuss mitigation of the phototoxic liability of biaryl derivatives on the basis of the HOMO-LUMO gap hypothesis during the course of optimization efforts.

Discovery of a Novel Series of N-Phenylindoline-5-sulfonamide Derivatives as Potent, Selective, and Orally Bioavailable Acyl CoA:Monoacylglycerol Acyltransferase-2 Inhibitors.

Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has attracted interest as a novel target for the treatment of obesity and metabolic diseases. Starting from N-phenylbenzenesulfonamide derivative 1 with moderate potency for MGAT2 inhibition, we explored an effective location of the hydrophobic group at the 1-position to enhance MGAT2 inhibitory activity. Shifting the hydrophobic group to the adjacent position followed by introduction of a bicyclic central core to restrict the substituent orientation produced N-phenylindoline-5-sulfonamide derivative 10b, which displayed much improved potency, with an IC50 value of 1.0 nM. This compound also exhibited excellent selectivity (greater than 30,000-fold) against related acyltransferases (MGAT3, DGAT1, DGAT2, and ACAT1). Subsequent optimization efforts were directed toward improving pharmacokinetic profiles, which resulted in the identification of 5-[(2,4-difluorophenyl)sulfamoyl]-7-(2-oxopyrrolidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indole-1-carboxamide (24d) endowed with potent MGAT2 inhibitory activity (IC50 = 3.4 nM) and high oral bioavailability (F = 52%, mouse). In a mouse oral fat tolerance test, oral administration of this compound effectively suppressed the elevation of plasma triacylglycerol levels.

Multilayer silicene nanoribbons.

The synthesis of silicene, graphene-like silicon, has generated very strong interest. Here, we reveal the growth of high aspect ratio, perfectly straight, and aligned silicon nanoribbons, exhibiting pyramidal cross section. They are multistacks of silicene and show in angle-resolved photoemission cone-like dispersion of their π and π* bands, at the X[overline] point of their one-dimensional Brillouin zone, with Fermi velocity of ~1.3 × 10(6) m sec(-1), which is very promising for potential applications.

Octithiophene on Cu(III) and Au(III): formation and electronic structure of molecular chains and films.

Adsorption and electronic structure of octithiophene (8T) molecules on Cu(III) and Au(III) surfaces are investigated using scanning tunneling microscopy (STM) and spectroscopy (STS) at room temperature. We find a large difference in adsorption behavior of 8T molecules on the two surfaces. At the initial stage of adsorption, 8T molecules are stabilized in the form of molecular chain on a terrace of Cu(III), whereas neither such chain structure nor isolated 8T molecules have been observed on a terrace of Au(III). By increasing the amount of adsorbed molecules, a disordered monolayer film is formed on Cu(III) while a well-ordered monolayer film is formed on Au(III). From the spectroscopic investigations using bias-dependent STM images and STS spectra and by comparing the data with theoretical calculations, it is found that the electronic property of 8T molecules in the molecular chain on Cu(III) is different from that of a free-standing 8T molecule while that in the monolayer film on Au(III) keeps original character of the free-standing 8T molecule. The present study shows that adsorption of 8T molecules on Cu(III) results in a formation of adsorption-induced states near the Fermi level.

Development and application of multiple-probe scanning probe microscopes.

In the research of advanced materials based on nanoscience and nanotechnology, it is often desirable to measure nanoscale local electrical conductivity at a designated position of a given sample. For this purpose, multiple-probe scanning probe microscopes (MP-SPMs), in which two, three or four scanning tunneling microscope (STM) or atomic force microscope (AFM) probes are operated independently, have been developed. Each probe in an MP-SPM is used not only for observing high-resolution STM or AFM images but also for forming an electrical contact enabling nanoscale local electrical conductivity measurement. The world's first double-probe STM (DP-STM) developed by the authors, which was subsequently modified to a triple-probe STM (TP-STM), has been used to measure the conductivities of one-dimensional metal nanowires and carbon nanotubes and also two-dimensional molecular films. A quadruple-probe STM (QP-STM) has also been developed and used to measure the conductivity of two-dimensional molecular films without the ambiguity of contact resistance between the probe and sample. Moreover, a quadruple-probe AFM (QP-AFM) with four conductive tuning-fork-type self-detection force sensing probes has been developed to measure the conductivity of a nanostructure on an insulating substrate. A general-purpose computer software to control four probes at the same time has also been developed and used in the operation of the QP-AFM. These developments and applications of MP-SPMs are reviewed in this paper.

A quadruple-scanning-probe force microscope for electrical property measurements of microscopic materials.

Four-terminal electrical measurement is realized on a microscopic structure in air, without a lithographic process, using a home-built quadruple-scanning-probe force microscope (QSPFM). The QSPFM has four probes whose positions are individually controlled by obtaining images of a sample in the manner of atomic force microscopy (AFM), and uses the probes as contacting electrodes for electrical measurements. A specially arranged tuning fork probe (TFP) is used as a self-detection force sensor to operate each probe in a frequency modulation AFM mode, resulting in simultaneous imaging of the same microscopic feature on an insulator using the four TFPs. Four-terminal electrical measurement is then demonstrated in air by placing each probe electrode in contact with a graphene flake exfoliated on a silicon dioxide film, and the sheet resistance of the flake is measured by the van der Pauw method. The present work shows that the QSPFM has the potential to measure the intrinsic electrical properties of a wide range of microscopic materials in situ without electrode fabrication.

Angled long tip to tuning fork probes for atomic force microscopy in various environments.

We expand the range of applications of a tuning fork probe (TFP) in frequency-modulation atomic force microscopy (FM-AFM) by attaching a long metal tip at a certain angle. By the combined flexure of the metal tip and the tuning fork prong, this TFP can change the direction of the detectable force by switching the resonance frequency, which has not been realized with conventional TFPs with short tips. The oscillatory behavior of the tip apex of the TFP is predicted by computer simulations and is experimentally confirmed with scanning electron microscope. FM-AFM operations using this TFP are performed in various environments, i.e., in ultrahigh vacuum, air, and water. FM-AFM images obtained at an atomic step of highly oriented pyrolytic graphite in air show a clear difference depending on the excitation frequency. It is also revealed that the higher order flexural modes of this TFP are advantageous for FM-AFM in water due to the reduction in the degree of hydrodynamic damping.

Rasmussen syndrome: multifocal spread of inflammation suggested from MRI and PET findings.

BACKGROUND: A 6-year-old girl with Rasmussen syndrome (RS) showed multiple small high-signal-intensity areas independently in the right hemisphere by fluid-attenuated inversion recovery (FLAIR) imaging on magnetic resonance imaging (MRI) 1 year after the onset of epilepsy. METHODS: MRI performed 4 months later demonstrated a further increase in the number of these foci and enlargement in the size of the previous FLAIR lesions. RESULTS: An [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) study showed a strong, spotty uptake in the right temporooccipital regions, corresponding to the sites of continuous EEG seizure discharges. In contrast, [11C]methionine PET demonstrated multifocal uptake regions, which corresponded anatomically to the FLAIR lesions, suggesting sites of underlying chronic inflammation. CONCLUSIONS: These neuroimaging findings suggested that the inflammatory process in RS spreads either multifocally at the same time, as seen in this case, or from one discrete area to the adjacent region, as reported previously.