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HSL inhibition is a promising approach to the treatment of dyslipidemia. As a result of re-optimization of lead compound 2, we identified novel compound 25a exhibiting potent inhibitory activity against HSL enzyme and cell with high selectivity for cholinesterases (AChE and BuChE). Reflecting its potent in vitro activity, compound 25a exhibited antilipolytic effect in rats at 1mg/kg p.o., which indicated that this novel compound is the most potent orally active HSL inhibitor. Moreover, compound 25a did not show bioactivation liability.

We report herein the synthesis and structure-activity relationships (SAR) of a series of pyridazine derivatives with the activation of glucose transporter type 4 (GLUT4) translocation. Through a cell-based phenotype screening in L6-GLUT4-myc myoblasts and functional glucose uptake assays, lead compound 1a was identified as a functional small molecule. After further derivatization, the thienopyridazine scaffold as the central ring (B-part) was revealed to have potent GLUT4 translocation activities. Consequently, we obtained promising compound 26b, which showed a significant blood glucose lowering effect in the severe diabetic mice model (10-week aged db/db mice) after oral dosing even at 10 mg/kg, implying that our pyridazine derivatives have potential to become novel therapeutic agents for diabetes mellitus.

Hormone sensitive lipase (HSL) is an attractive therapeutic target of dyslipidemia. We designed and synthesized several compounds as reversible HSL inhibitors with a focus on hydrophobic interactions, which was thought to be effective upon the HSL inhibitory activity. In these efforts, we identified boronated compound 12 showing a potent HSL inhibitory activity with an IC50 value of 7nM and a high selectivity against cholinesterases. Furthermore, compound 12 is the first boron containing HSL inhibitor that has shown an antilipolytic effect in rats after oral administration at 3mg/kg.

Novel pyrrole derivatives were discovered as potent agonists of the niacin receptor, GPR109A. During the derivatization, compound 16 was found to be effective both in vitro and in vivo. The compound 16 exhibited a significant reduction of the non-esterified fatty acid in human GPR109A transgenic rats, and the duration of its in vivo efficacy was much longer than niacin.

Hormone sensitive lipase (HSL) has emerged as an attractive target for the treatment of dyslipidemia. We previously reported compound 1 as a potent and orally active HSL inhibitor. Although an attractive profile was demonstrated, subsequent studies revealed that compound 1 has a bioactivation liability. The oxygen-carbon linker in compound 1 was identified as being potentially responsible for reactive metabolite formation. By exchanging of this susceptible fragment was feasible, and a benzanilide derivative 6b with a decreased bioactivation liability was obtained. Further modification of the novel benzanilide scaffold resulted in the identification of compound 24b. Compound 24b exhibited potent HSL inhibitory activity (IC50=2nM) with a significantly reduced bioactivation potential. Oral administration of compound 24b exhibited an antilipolytic effect on rats at 3mg/kg.

We describe the design, syntheses, and structure-activity relationships of novel zwitterionic compounds as nonthiazolidinedion-based peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists. In our previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a sufficient glucose-lowering effect in db/db mice. However, this compound possessed an issue, i.e., the 1,3,4-oxadiazole ring was not stable in acidic conditions. Thus, we carried out further optimization to improve the stability while maintaining the other favorable profile features including potent PPARα/γ dual agonistic activity. We addressed the issue by changing the oxadiazole ring to a bioisostere amide group. These amide derivatives were stable in acidic conditions and decreased plasma glucose and plasma triglyceride levels significantly without marked weight gain.

Thermally-induced structural relaxation of amorphous silicon-germanium (a-Si1-xGex) alloys has been examined using molecular-dynamics (MD) simulations with the Tersoff interatomic potential. The a-Si1-xGex networks were successfully observed in the present MD simulations. Major changes in the topological short-range order upon annealing occurred within the second coordination shell, while the chemical short-range order was not altered. It was found that the decrease in potential energy associated with the change in the standard deviation of bond angles becomes large as the Ge composition increases. This result was consistent with the heat release due to structural relaxation, which was observed experimentally. We also examined differences in the phonon densities of states between the as-quenched and annealed a-Si1-xGex alloys.

Although extensive studies have been carried out on structural analyses of amorphous silicon-germanium (a-Si1-xGex) alloys, there are still controversies concerning short-range order in a-Si1-xGex alloys. In this study, we examined amorphous structures of Si1-xGex alloys by molecular-dynamics (MD) simulations using the Tersoff interatomic potential. Amorphous networks were prepared by rapid quenching from liquid Si1-xGex alloys. Computer-generated atomic configurations consisted of tetrahedral networks with complete chemical disorder in the first coordination shell. The bond lengths of Si-Si, Si-Ge and Ge-Ge pairs slightly increased with the Ge composition, and a weaker composition dependence was observed in the bond lengths of Si-Si and Si-Ge pairs than that for Ge-Ge pair. These results were in good agreement with those obtained experimentally, suggesting that the MD calculations based on the Tersoff potential is useful for the structural analysis of a-Si1-xGex alloys. It was confirmed that the Ge-Ge bond length and bond angle surrounding Ge atoms are more distorted. This is attributed to the difference between Si and Ge in the bond-stretching and in the bond-bending forces.

ABSTRACT To detect a small population of blood cells with a deficiency of glycosyl phosphatidylinositol (GPI)-anchored protein, we evaluated the expression of CD59 by flow cytometry on one million erythrocytes, which is about 100 times more than the number of erythrocytes tested by our standard immunoassay. Blood samples from healthy volunteers, patients with aplastic anemia (AA), and patients with myelodysplastic syndrome (MDS), who all showed no detectable GPI deficiency by the standard assay, were investigated. The numbers of CD59-deficient erythrocytes were 5 to 145/10 6 erythrocytes in the healthy volunteers (mean 29.2), and one of the volunteers had an increase in the deficient cells exceeding the mean + 3 SD (141.7), a normal limit. A CD59-deficient population was detected in 6 of the 21 (28.6%) patients with AA and 5 of the 18 (27.8%) patients with MDS. The new assay was performed again in 5 of these 11 patients and the normal individual who had the CD59-deficient populations at 6 and 12 months after the initial study. The number of deficient cells gradually increased in 1 patient with MDS (from 511 to 2892/10 6 erythrocytes), while the numbers of the other 4 patients showed a tendency to decline, although the deficient populations were repeatedly detected on most of the occasions. Changes in the number of the deficient cells were also seen in the healthy volunteer, but they were rather rapid; the numbers changed from 145 to 5661 and then to 18/10 6 erythrocytes within 3 months. The CD59 assay used in this study is easy to perform and enabled us to detect less than 1% GPI-deficient cells.

Polyclonal B lymphocytosis was found in four patients having clinical and hematologic features resembling those of hairy cell leukemia (HCL). All four patients were women between 37 and 67 years of age. Three patients had splenomegaly. Lymphadenopthy was absent or slight. Persistent lymphocytosis was seen in all the patients, and anemia and/or thrombopenia was observed in three of the patients. Abnormal lymphocytes have long microvilli and prominent membranous ruffles on their surfaces. Bone marrow aspirates and biopsy specimens showed increased numbers of abnormal lymphocytes with round nuclei and abundant pale cytoplasm. Although these findings were similar to those of HCL, studies of Ig gene rearrangements and expression showed the polyclonal proliferation of B cells. We called this new disease hairy B-cell lymphoproliferative disorder (HBLD). All four patients exhibited a polyclonal increase in serum IgG. The morphology of the cells in HBLD was more similar to that of leukemia cells of a variant form of HCL (HCL-Japanese variant) than to typical HCL cells. The surface IgG+, CD5−, CD11c+, CD22+, CD24−, CD25− phenotype and the weak tartrate-resistant acid phosphatase activity in the cells were identical to those of HCL cells of the Japanese variant. Our findings suggest that the B cells in HBLD are the nonmalignant counterpart of leukemic B cells in HCL-Japanese variant.

Cytosolic-nuclear tumor promoter-specific binding protein (CN-TPBP) was photoaffinity-labeled with a specific ligand, 3beta,5alpha-dihydroxycholestan-6-one (YS-64). Analysis by ODS-HPLC of peptide fragments obtained from the labeled CN-TPBP by trypsinization indicated the existence of a single specifically labeled site. Affinity gels for the purification of CN-TPBP were then prepared. As ligands for the affinity gels, 12-O-tetradecanoylphorbol 13-acetate (TPA), a typical phorbol-type tumor promoter, and benzolactam-V8-310 (BL-V8-310), a structural/biological mimic of teleocidin-class tumor promoters, were adopted. The use of these gels afforded a protein that showed a single band of 58 kDa on SDS-PAGE.

We describe herein the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. In the previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a great glucose lowering effect in the db/db mice. However, this compound possessed fatal issues such as potent cytochrome P450 (CYP)3A4 direct inhibitory activity. Thus, we carried out the medicinal optimization to improve these while maintaining the potent PPAR agonistic activity. As a result, the issues were addressed by changing the furan ring to a low lipophilic 1,3,4-oxadiazole ring. Additionally, these oxadiazole derivatives exhibited a significant decrease in plasma glucose and plasma triglyceride levels without marked weight gain.

This case report describes a young male patient with recurrent abdominal pain persisting for more than 16 months. Clinical investigations showed signs of inflammation and pancytopenia. A diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) was made 9 months after the onset of the abdominal pain, following endoscopic examinations that revealed evidence of a previously unknown hemorrhage. Regular monitoring indicated that the abdominal pain was associated with elevations in lactate dehydrogenase, C-reactive proteins, and D-dimer levels. The patient started treatment with the complement inhibitor eculizumab shortly after it was approved for use in Japanese PNH patients with hemolysis. Resolution of the abdominal pain and normalization of clinical parameters were noted within 3 weeks from treatment initiation.

We describe here the design, syntheses and structure–activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. We commenced the medicinal research with compound 1 originated by Eli Lilly, which was reported to possess PPAR α/γ dual agonist activity. We incorporated an amine linker and optimized it on the nitrogen of the linker, thereby envisioning the enhancement of the PPAR α/γ dual agonist activity together with altering the physicochemical properties. As a result, we could generate compounds showing the PPAR α/γ dual activity, especially among which compound 22e had a franylmethyl group on the linker and 2,6-dimethyl phenyl ring at the carboxylic acid head group furnishing a highly potent dual agonist activity, together with a great glucose lowering effect. Moreover, it remedied the lipid profile, that is, triglyceride without body weight gain in the db/db mice model.

We report a death case of a man in his sixties with pneumocystis pneumonia during chemotherapy for gastric cancer. He was diagnosed with cStage IIIB (T4a, N2, H0, P0, M0). Because of bulky N2, systemic chemotherapy of S-1 and CDDP was performed from April 2009. But no reductions were noted after 2 courses. We next treated this patient with S-1 and CPT-11. He had also received corticosteroid treatment for nausea. Because of high fever and choke, he came to our hospital at day 12 in 3 courses, and a severe respiratory failure occurred. CT of the chest showed diffuse ground-glass bilateral opacities, and we immediately started a treatment with trimethoprim-sulfamethozazole and corticosteroid for the possibility of pneumocystis pneumonia. We finally deduced pneumocystis pneumonia from markedly elevated serum beta-D-glucan and PCR positive after hospitalization. In spite of early treatments, he died of bacterial pneumonia and gastric cancer. We should be careful of pneumocystis pneumonia during chemotherapy and corticosteroid treatment.

(-)-Benzolactam-V8-310 reproduces the active conformation and biological activity of teleocidins. Various sizes and shapes of alkyl groups on aromatic nucleus of BL-V8 were synthesized as optically pure forms. Structure-activity results indicate that hydrophobic substituents at C-9 position plays a critical role for the appearance of biological activities

In the early 1990's, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity.

(-)-Benzolactam-V8-310 reproduces the active conformation and biological activity of teleocidins. Various sizes and shapes of alkyl groups on aromatic nucleus of BL-V8 were synthesized as optically pure forms. Structure-activity results indicate that hydrophobic substituents at C-9 position plays a critical role for the appearance of biological activities

Structural and dynamical properties of amorphous silicon-germanium (a-Si 1 - x Ge x ) alloys have been examined by molecular dynamics simulations using the Tersoff interatomic potential. Amorphous networks were generated byrapid quenching from liquid Si 1 - x Ge x alloys. Good agreement was obtained between the simulated and experimentally measured radial distribution functions and phonon densities of states, suggesting that the Tersoff potential is useful for analyzing the atomic configurations and vibrational properties of a-Si 1 - x Ge x alloys. Local atomistic structures, such as topological and chemical short-range order states, were also examined in detail, and we compared them with experimental and theoretical results reported previously. On the basis of the results obtained here, we proposed that the bond length and bond angle around Ge atoms have more distortion than those around Si atoms in a-Si 1 - x Ge x networks.

A 51-year-old man was diagnosed as having Philadelpha (Ph) chromosome-positive acute myeloid leukemia (AML) with major-BCR/ABL mRNA. He achieved complete remission after induction chemotherapy. Five months later, he was again positive for the Ph chromosome despite additional chemotherapy. He was therefore treated with imatinib mesylate, a specific inhibitor of BCR/ABL tyrosine kinase, at a dose of 600 mg/day. However, the treatment was interrupted because of thrombocytopenia, skin eruption and face edema. After the patient recovered from these side effects, imatinib was readministered at a dose of 400 mg/day and a complete cytogenetic response was achieved. Imatinib is expected to be an effective drug for Ph chromosome-positive AML.

We have designed and synthesized estrogen antagonists bearing dicarba-closo-dodecaborane (carborane) as a hydrophobic pharmacophore based on the structure of 1-(4-hydroxyphenyl)1,12-dicarba-closo-dodecaborane, a potent estrogen agonist that we reported previously. Compounds with a long alkyl chain bearing an amide moiety on the carborane skeleton (6, 7) showed estrogen antagonistic activity in a luciferase reporter gene assay using COS-1 cells transfected with a rat ERa-expression plasmid and as an appropriate reporter plasmid.

3 beta,5 alpha-Dihydroxycholestan-6-one was detected in fresh human plasma at the concentration of 14-44 ng/mL. The oxysterol binds specifically to phorbol ester specific binding protein in vitro, and may be an endogenous ligand of the protein.

The improved routes to prepare tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylic acid lithium salts (2 and 3) were developed. Route A is consisted of the improved preparation of thiazolopyridine intermediates, and Route B is applicable for a large scale synthesis of tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid derivatives. The methods we developed may serve as facile means for preparing thiazolopyridine and tetrahydrothiazolopyridine derivatives.

Hairy cell leukemia (HCL) is an uncommon type of chronic B cell leukemia mainly affecting middle-aged adults. HCL presenting with pancytopenia is rare in Japan and a distinct subtype of HCL termed HCL-Japanese variant is predominantly seen. We describe a HCL patient with unusual presentation. The patient was a 26-year-old male, such early onset of HCL being quite rare. The patient showed leukocytosis with many circulating hairy cells and cellular bone marrow. These findings were preferentially seen in HCL-Japanese variant, but, cytomorphologic, cytochemical and immunophenotypical studies on the pathologic cells were consistent with those of typical HCL seen in Western countries. Interferon-alpha therapy was very effective in this case. Differentiation of the subtype of HCL appears to be important for the choice of the treatment. The cytological findings were useful for the differential diagnosis of HCL presenting with leukocytosis.

The method of CO2-laser-microwave double resonance (LMDR) with an intense electric field was used to measure Stark shifts of ground-state microwave transitions of D2CO. Thirty LMDR signals originating from 15 K-doublet transitions were observed, associated with the infrared transitions of the ν4 and ν6 bands. Least-squares analysis of the observed LMDR signals yields precise values of the coefficients in the dipole-moment expansion, μ0 + μJJ(J + 1) + μKK2: μ0, 2.347 134(8) D; μJ, −4.76(10) × 10−6 D; μK, −28.7(18) × 10−6 D; where one-standard-deviation uncertainties are given in parentheses. The infrared–infrared double-resonance signals of PH3, which were calibrated against the OCS dipole moment, were used for the electric-field calibration, allowing us to determine the dipole moment with a precision of 10 parts in 106 (ppm). However, the absolute accuracy of the dipole moment obtained is 50 ppm, as limited by the uncertainty of the OCS dipole moment. The effective dipole moment for the 11,0 ← 11,1 transition measured in the present study agrees well with the effective dipole moment for the 11,0 rotational level from a molecular-beam electric resonance experiment. The μJ and μK coefficients calculated from Watson’s θγαβ constants agree well with the experimental values.