N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent

3-?4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl?-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-?4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl?propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-?4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl? ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.     

Effects of inhibitor of protein kinase C on brain edema formation evoked by experimental cerebral ischemia in gerbils and rats

Recent studies have suggested that protein kinase C (PKC) may be involved in the formation of brain edema. In this paper, the effects of two kinds of PKC inhibitors, H-7 and matrine, were examined on the brain edema formation in experimental models. The results showed that pretreatment with H-7 6.25 and 12.5 mg.kg-1 prevented the accumulation of water and certain electrolytes in the unilateral hemisphere of the brain evoked by ligation of a single common carotid artery in Mongolian gerbil; pretreatment with matrine 25 and 50 mg.kg-1 reduced the extent of cerebral edema formation evoked by ligation of a single common carotid artery in gerbil and by middle cerebral artery occlusion in Sprague-Dawley rats. These results present new evidence for the involvement of PKC in the formation of brain edema.     

High-performance optical phase modulation using piezoelectricZnO-coated standard telecommunication fiber

Optical phase modulation in a standard telecommunication fiber coated with a piezoelectric ZnO jacket has been investigated both experimentally and theoretically. The frequency response of the modulator exhibits 18 peaks between 20 and 800 MHz, which correspond to radial resonances of the coated fiber composite. A theoretical model was developed to explain the experimental results. The model takes into account the geometry of the modulator, nonuniform strain distributions, and the structure of the ZnO film. The calculated positions of the resonances and cancellation of phase modulation at frequencies higher than 800 MHz agree well with the measured data. The analysis also demonstrates the capability of tuning the resonances positions by varying the thickness of the ZnO jacket or the metal electrodes     

The recombinant Klebsiella pneumoniae outer membrane protein OmpA has carrier properties for conjugated antigenic peptides

Klebsiella pneumoniae OmpA, the 40-kDa major protein of the outer membrane, was cloned and expressed in Escherichia coli. The recombinant protein was produced intracellularly in E. coli as inclusion bodies. Fusion of a short peptide to the N-terminus of native P40 facilitated high-level expression of the recombinant protein. Purified recombinant P40 was analyzed to verify purity and structural integrity. The molecular mass of purified recombinant P40 determined by electrospray mass spectrometry was 37,061 Da, in agreement with the theoretical mass deduced from the DNA sequence. Specific proliferation of recombinant-P40-primed murine lymph node cells in response to recombinant P40 stimulation in vitro indicated the presence of a T-cell epitope on recombinant P40. The induction of high serum antibody titers to a synthetic peptide derived from the attachment protein G of the respiratory syncytial virus when chemically coupled to recombinant P40 indicated that the protein had potent carrier properties.     

ETude cinetique des systemes Cd---Cd(II) et Fe(II)---Fe(II) en milieu aqueux par trace d'oscillogrammes lineaires au moyen de la methode de double impulsion potentiostatique

The principle and construction of a quadratic function generator are described. The voltage output, supplying the oscilloscope time-base, gives a linear i(√t) oscillogram and allows the transfer cd i_a to be read on the oscilloscope screen.

The kinetic parameters of the Cd---Cd(II0 and Fe(II)---fe(III) sytsems are determined in this way. In these two examples, the second Fick equation is solved numerically in order to establish the validity of the formula used to calculate T₀, the time corresponding to the cd i_a.

Zusammenfassung

Man beschreibt die Einstellung von einem Quadratischfunktiongenerator. Wenn die Klemmenspannung dieses Generators mit der Zeitablenkung des Oszillographes angeschaltet wird, erreicht man ein lineares Oszillogramm i(√t); die Durchtrittstromdichte i_a wird sofort auf dem Oszilloskopschrim gelesen.

Mann kann mit dieser Methode die elektrolytischen Konstanten der Reaktionen Cd---Cd(II) und Fe(II)---Fe(III) bestimmen. Jedenfalls integriert man die Zweite Diffusion differentialgleichung zahlenmässig und so, kann man die Richtigkeit der die Zeit gebenden Formel, welcher Zeit die Ordinate i_a auf die Linie i(√t) entspricht, bestätigen.     

Differential characteristics of the electrocardiogram in early repolarization and acute pericarditis

Electrocardiographic mimicry necessitates differentiation between acute pericarditis and early repolarization. Among 96 persons, limb-lead RST deviations occurred in all 48 with pericarditis, but only 27 with early repolarization. RS-T vectors (A RS-T) in pericarditis tended to be horizontal (25 patients) and left of the T vector, A T (28 patients); in early repolarization, A RS-T was vertical in 15 subjects and right of A T (20 subjects); P less than or equal to 0.01. RS-T depression in Lead V1 was more common in pericarditis (14 vs. two); isoelectric RS-T in Lead V6 was more common in early repolarization (10 vs. one); P less than or equal to 0.01. PR segment deviations occurred in both limb and precordial leads in pericarditis; in early repolarization they were confined to either lead group. Thus, R-ST deviations in both limb and precordial leads with horizontal A RS-T to left of A T and RS-T depression in Lead V1 favor pericarditis; vertical A RS-T and isoelectric RS-T in Lead V6 favor early repolarization.     

Reevaluation of the linkage between acute hemorrhagic shock and bacterial translocation in the rat

The present study was undertaken to determine the conditions under which acute periods of hemorrhagic shock induce bacterial translocation. Rats (at least six per group) were anesthetized intraperitoneally with the barbiturate, pentobarbital (50 or 65 mg/kg), or the inhalation anesthetic methoxyflurane. Following anesthesia, the femoral artery was catheterized, from which blood was withdrawn to maintain a mean arterial blood pressure of 30 mmHg for 30, 60, or 90 min, followed by reinfusion of shed blood. Instrumented, but nonshocked animals served as controls. Rats were sacrificed at 0, 2, or 24 hr postshock, and quantitative bacterial cultures of the mesenteric lymph node complex (MLN), liver, and spleen were made. Within groups, the effects of heparinization were also determined. In pentobarbital-treated animals, regardless of the extent of heparinization, consistent translocation to both MLN and distant organs occurred when shock was prolonged for 90 min, and assessment of translocation was made 24 hr after reinfusion of shed blood. Furthermore, a mortality rate of approximately 30% was found in rats subjected to this protocol. The magnitude of translocation was less consistent, and did not differ from that in sham shock controls, under other conditions of shock and evaluation. In rats anesthetized with methoxyflurane, no mortality occurred, and no statistical significance between the incidence or degree of translocation in shocked animals vs. sham shock controls could be demonstrated, regardless of the shock protocol. In additional studies, effects of these anesthetics on intestinal morphology and superior mesenteric arterial (SMA) flow in the context of hemorrhagic shock were assessed.(ABSTRACT TRUNCATED AT 250 WORDS)