A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 4. Discovery of novel frameworks mimicking the active conformation

In recent articles we reported the identification of a series of 8-[[2, 6-dichloro-3-[N-methyl-N-[(E)-(substituted)acryloylglycyl]amino]++ +benzy l]oxy]-2-methylimidazo[1,2-a]pyridines as the first orally active non-peptide bradykinin (BK) B2 receptor antagonists. Optimization of the terminal glycine part and the imidazo[1,2-a]pyridine moiety led to the discovery of a clinical candidate (5, FR173657). With the aim of completion of the structure-activity relationship (SAR) study, we next investigated the roles of the substituents on the central phenyl ring. The results suggested that the 2,6-dichloro or 2, 6-dimethyl groups may play important roles in regulating the conformations of the 1- and 3-substituents and also may interact with hydrophobic pockets of the B2 receptors. Furthermore, according to the results of a molecular modeling study reported in part 1 of this series, we designed and synthesized a series of sterically constrained analogues by replacing the N-methylamide group with cis-amide-like rigid moieties. We discovered several bioisosteres and chemically proved that the N-methylamide moiety adopts the cis-amide form in the active conformation. Extensive chemical modification led to the identification of a novel class of highly potent and orally active non-peptide B2 antagonists represented by a pyrrole derivative (52a, FR193517). Compound 52a inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50s of 0.37 and 0.56 nM, respectively. This compound also displayed excellent in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs at 1 mg/kg by oral administration.     

Generation mechanism and evaluation of overall raster moiré patterns on color CRTs

Abstract— An evaluation technique of overall raster moiré patterns on color CRTs is developed. The technique can simulate any of the moiré modes. Generation mechanisms of various moiré patterns are clarified using the technique. It is found that the moiré patterns, no matter how complicated, consist of four basic types: barrel, pincushion, elliptical, and hyperbolic types. The patterns are found to be sensitive to the scan line distribution. When the scan lines are curved, the pattern appearing on the upper screen is different from that on the lower screen. When the scan lines are tilted, the patterns have horizontal shifts. By observing the moiré patterns, the scan line distribution can be estimated precisely.     

R dependence of electronic structure in perovskite type structure compounds, RBRh3 (R: Sc, Y and La)

The electronic structures of perovskite type structure, RBRh₃ (R: Sc, Y and La) were studied by X-ray photoelectron spectroscopy and calculation with full potential linearized augmented plane wave (FLAPW) method. As the lattice constant of the crystals increases with the atomic number of R, it can be discussed how the bond length between boron and rhodium atoms effect on the bonding character. The valence band XPS profiles of the samples are well coincided with the calculated profiles. The calculated electron density maps of the valence bands indicate the following. The charge transfer directions are from R to rhodium atoms and from boron to rhodium atoms. The bonds of RRh and BRh atoms have also covalent character. The covalency of RRh bond increases with the order of the atomic number of R atoms. On the other hand, the covalent bond of BRh decreases with the order atomic number.     

Beta-Glucosylceramide Administration (i.p.) Activates Natural Killer T cells In Vivo and Prevents Tumor Metastasis in Mice

Natural killer (NK) T cells are well known to play important roles in both tumor rejection and the defense against infectious. Therefore, the antitumor potential of NKT cell-activating antigens have been the focus for the development of NKT cell-based immunotherapies. Up to now, several studies have revealed that the administrations of glycolipids (e.g. α-galactosylceramide) can successfully treat certain metastatic tumors. However, liver injuries appeared upon the application of these antigens. We previously examined the potential of using β-glucosylceramide (β-GlcCer) to inhibit tumor metastasis to the liver. The aim of this study was to determine the antimetastatic effects of β-GlcCer and its impact on the activation of NKT cells. Intraperitoneal administration of β-GlcCer enhanced the production of interferon-γ from hepatic lymphocytes containing NKT cells, and increased the cytotoxicity of hepatic lymphocytes against tumor cells. Moreover, β-GlcCer administration suppressed the hepatic metastasis of tumors in wild type (WT) mice, but not in CD1d (-/-) or Jα18 (-/-) mice. The drawback associated with the other glycolipids in liver injury was not noted in WT mice treated with the continuous daily administration of β-GlcCer for 2 weeks. The present study demonstrated that β-GlcCer treatment activates invariant NKT cells, thus resulting in the inhibition of tumor metastasis.     

Relation between static and dynamic Young's modulus of nuclear graphites and carbon

In order to evaluate precisely the stresses and strains generated in the graphite structures of high temperature gas-cooled reactors (HTGRs), it is necessary to use not only correct stress-strain relationships but also proper values of the Young's modulus of HTGR graphites. In this study the relation between the Young's modulus obtained from the slope of the stress-strain curve at the origin and that measured by the ultrasonic wave propagation method was examined on two grades of HTGR graphites (IG-110 and PGX) and a grade of carbon materials (ASR-ORB). One of the main conclusions obtained here is that the ratio of the static Young's modulus to the dynamic one depends upon the accuracy of the strain measurement. If the Young's modulus which is evaluated from the secant at 0.01 to 0.05% strain is taken as the static modulus, the dynamic Young's modulus measured using a 5-MHz transducer is approximately equal to the static one.     

40 Gbit/s n-i-n InP Mach-Zehnder modulator with a /spl pi/ voltage of 2.2 V

Using an n-i-n heterostructure, a travelling-wave Mach-Zehnder modulator on an InP substrate has been developed. An extremely small /spl pi/ voltage (V/sub /spl pi//) of 2.2 V has been obtained, even for a short signal-electrode length of 3 mm. Wavelength-insensitive extinction characteristics and 40 Gbit/s operation are described.     

Study on mo steel for high temperature gas-cooled reactor material characterization of forged low Si mo steel

The Japan Atomic Energy Research Institute (JAERI) has carried out a series of research and development work related to the high temperature gas-cooled reactor (HTGR) and, accordingly the high temperature engineering test reactor (HTTR) will be constructed in the near future. As the reactor pressure vessel (RPV) material, Mo steel will be used. Material characterization tests have been carried out to evaluate the applicability of the Mo steel for the RPV and to prepare for the licensing. The present paper summarizes the fracture toughness behavior including K_Id and K_Ia, irradiation embrittlement susceptibility and degradation of steel due to the long term aging at high temperature of the forged low Mo steel. These tests reveal good fracture toughness which well meets the requirements of the ASME Code, low neutron irradiation embrittlement susceptibility, little embrittlement by long term aging and so on. The present test results demonstrate good applicability of forged low Mo steel to the RPV of HTGR.