Seiji Ogawa

Total synthesis and bioactivity of resolvin E2

Resolvin E2 is a potent anti-inflammatory compound, derived from eicosapentaenoic acid. The efficient total synthesis of resolvin E2 by taking advantage of its intrinsic pseudoenantiomeric substructures is reported. The synthetic resolvin E2 proved to be biologically active in blocking neutrophil infiltration and reducing proinflammatory cytokines in the acute peritonitis model.

Successful surgical treatment for spontaneous retroperitoneal hematoma in polycythemia vera: report of a case.

Bleeding is a common complication of such myeloproliferative disorders as polycythemia vera, and it usually occurs in either the skin or mucosa. We experienced a case of a massive retroperitoneal hematoma with no history of trauma in association with polycythemia vera. A 68-year-old man was referred to our hospital as a case of acute abdomen, and was diagnosed as having a retroperitoneal hematoma and polycythemia vera based on radiological and hematological examinations. Because the mass effect of the hematoma caused a progressive deterioration of his respiratory condition, surgical drainage was necessitated and successfully undertaken. Although conservative treatment is reportedly sufficient and uncontrollable intraoperative bleeding may occur, especially in cases of myeloproliferative disorders, our experience suggests that an operation may nevertheless be occasionally advisable for this rare condition.

Synthesis and evaluation of novel modified γ-lactam prostanoids as EP4 subtype-selective agonists

To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified γ-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the γ-hydroxycyclopentanone without a troublesome 11-hydroxy group were identified as highly subtype-selective EP4 agonists. Among the tested, several representative compounds demonstrated in vivo efficacy after oral dosing in rats. Their pharmacokinetic and structure-activity relationship studies are presented.

Electronic structure of Bi2Sr2CaCu2O8 by photoemission and brehmsstrahlung isochromat spectroscopy

Abstract The electronic structure of Bi 2 Sr 2 CaCu 2 O 8 both above and below the Fermi level has been investigated by photoemission and Bremsstrahlung isochromat (BIS) spectroscopy. A state 2.2 eV above the Fermi level is assigned to the Cu 3d 10 band. A comparison with recent optical reflectivity studies shows that most interband transitions greater than ≈ 2 eV may be assigned to excitations within the Bi-O planes. Significant energy shifts are observed in the reflectivity data due to a final state effect.

Discovery of G Protein-Biased EP2 Receptor Agonists

To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors.

Discovery of new orally active prostaglandin D2 receptor antagonists.

To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D(2) (PGD(2)) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human platelet rich plasma (hPRP), which is one of the indexes of DP antagonism. The optimization process including improvement of the physicochemical properties such as solubility, which may result in an improved pharmacokinetic (PK) profile, is presented. Optimized compounds were studied for their pharmacokinetics and in vivo potential. A structure-activity relationship study is also presented. Some of the test compounds were found to have in vivo efficacy towards the inhibition of PGD(2)-induced and OVA-induced vascular permeability in guinea pig conjunctiva.

Local destruction of antiferromagnetic spin correlation in high-Tc superconductor (La1−xSrx)2Cu0.99M0.01O4−z (M = Ga, Fe)

Abstract The origin of T c -supression in the impurity-doped high- T c superconductor (La 1− x Sr x ) 2 Cu 0.99 M 0.01 O 4− z ( M = Ga , Fe ) is investigated through the measurements of resistivity, magnetization and ESR. By substitution of Ga or Fe for 1% of Cu atoms, T c is depressed and maximum T c is shifted to higher Sr-concentration by about 0.5% and 1.0%, respectively. This shift can be attributed to hole reduction by doped trivalent ions and to magnetic pair breaking of Fe spins. Apparent effective moment per Fe in Fe-doped samples increases from 4.0 to 5.5 υ B with increasing Sr-concentration. This indicates that localized spin density is induced around Fe ions and couples antiferromagnetically with Fe spins but the spin density reduces with increasing itinerant hole carriers. It is suggested that the appearance of static spin density around doped Ga or Fe destroys antiferromagnetically correlated spin system on the CuO 2 plane, leading to T c -suppression.

Structural optimization and structure-functional selectivity relationship studies of G protein-biased EP2 receptor agonists.

The modification of the novel G protein-biased EP2 agonist 1 has been investigated to improve its G protein activity and develop a better understanding of its structure-functional selectivity relationship (SFSR). The optimization of the substituents on the phenyl ring of 1, followed by the inversion of the hydroxyl group on the cyclopentane moiety led to compound 9, which showed a 100-fold increase in its G protein activity compared with 1 without any increase in β-arrestin recruitment. Furthermore, SFSR studies revealed that the combination of meta and para substituents on the phenyl moiety was crucial to the functional selectivity.

Destruction of superconductivity and modulation of spin correlation in (La1−xSrx)2Cu1−yFeyO4−z

Abstract When superconductivity is destroyed by substitution of Fe for Cu in La-Sr-Cu system, variation of spin correlation on CuO2 plane is investigated through the measurements of electric resistivity, magnetic susceptibility, Mossbauer effect and EPR for the samples of (La1−xSrx)2Cu1−yFeyO4−z. With the increasing y at fixed x=0.09, electric conductivity decreases and Peff per Fe decreases from about 5.0 to 4.0, while with increasing x at fixed y=0.01, the electric conductivity rises and Peff per Fe increases from about 4.0 to 5.5. Tc suppression due to Fe-doping is more drastic than expected from pair breaking by Fe moment based on A.G. theory. It is suggested that destruction of superconductivity due to Fe-doping is attributable to not only Fe moment but also breaking of coherent spin singlet state on CuO2 plane.