Jin Sook Song

Pharmacokinetic characterization of decursinol derived from Angelica gigas Nakai in rats

Decursinol is a major coumarin derived from the roots of Angelica gigas and has various pharmacological effects against inflammation, angiogenesis, nociceptive pain and Alzheimer’s disease. In vitro and in vivo studies were conducted to characterize the metabolism and pharmacokinetics of decursinol. Decursinol exhibited high stability to oxidative and glucuronic metabolism in human and rat liver microsomes. In Caco-2 cell monolayers, decursinol showed high permeability (>14 × 10−6 cm/s) at all tested concentrations in the absorptive direction, which saturated at 100 μM. Secretion increased in a concentration-dependent manner, with an efflux ratio of more than 2 at 50 μM, indicating the participation of an active efflux transporter such as P-glycoprotein, multidrug resistance protein 2 or breast cancer resistance protein. The fraction of decursinol not bound to plasma proteins was 25–26% in the rat and 9–18% in humans. In human plasma, but not rat plasma, the percentage of unbound decursinol was concentration dependent. Following intravenous administration in rats, non-linear elimination of decursinol was observed with Km and Vmax values of 2.1 μg/mL and 2.5 mg·h−1·kg−1, respectively. Following oral administration, decursinol exhibited high oral bioavailability (>45%) and rapid absorption (Tmax, 0.4–0.9 h) over the dose range studied. In addition, dose-dependent absorption and elimination were observed at 20 mg/kg.

Synthesis and biological evaluation of aminobenzimidazole derivatives with a phenylcyclohexyl acetic acid group as anti-obesity and anti-diabetic agents.

A series of benzimidazole derivatives with a phenylcyclohexyl acetic acid group as DGAT-1 inhibitors was developed. Among the benzimidazole series, compound 5k showed submicromolar in vitro activity toward human and mouse DGAT-1, good selectivity toward DGAT-2, human liver metabolic stability, and pharmacokinetic (PK) and safety profiles such as hERG, CYP and acute toxicity. Additionally, 5k showed good in vivo efficacy in 4weeks study with DIO mouse model.

Discovery of carbohybrid-based 2-aminopyrimidine analogues as a new class of rapid-acting antimalarial agents using image-based cytological profiling assay.

New antimalarial agents that exhibit multistage activities against drug-resistant strains of malaria parasites represent good starting points for developing next-generation antimalarial therapies. To facilitate the progression of such agents into the development phase, we developed an image-based parasitological screening method for defining drug effects on different asexual life cycle stages of Plasmodium falciparum. High-throughput screening of a newly assembled diversity-oriented synthetic library using this approach led to the identification of carbohybrid-based 2-aminopyrimidine compounds with fast-acting growth inhibitory activities against three laboratory strains of multidrug-resistant P. falciparum. Our structure-activity relationship study led to the identification of two derivatives (8aA and 11aA) as the most promising antimalarial candidates (mean EC50 of 0.130 and 0.096 μM against all three P. falciparum strains, selectivity indices >600, microsomal stabilities >80%, and mouse malaria ED50 values of 0.32 and 0.12 mg/kg/day, respectively), targeting all major blood stages of multidrug-resistant P. falciparum parasites.

Synthesis and 11β hydroxysteroid dehydrogenase 1 inhibition of thiazolidine derivatives with an adamantyl group.

A new series of thiazolidine derivatives with an adamantyl group was synthesized and evaluated for their ability to inhibit 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). Our initial compound 5a showed a weak inhibitory activity. Significant improvements in potency were achieved by substituent modification. The potent compound 8g (E) showed good in vitro inhibitory activity toward human 11β-HSD1, selectivity toward 11β-HSD2, metabolic stability, pharmacokinetic, and safety profile. Furthermore, this compound significantly inhibited 11β-HSD1 activity in rat and monkey models, and showed improved glycemic control in KKAy mice.

Discovery of (2-Fluoro-Benzyl)-(2-Methyl-2-Phenethyl-2H-Chromen-6-yl)-Amine (KRH-102140) as an Orally Active 5-Lipoxygenase Inhibitor with Activity in Murine Inflammation Models

Objective and Design: We investigated anti-inflammatory properties of a novel 5-lipoxygenase (5-LO) inhibitor, KRH-102140, in vitro and in vivo. 5-LO enzyme activity was assayed using insect cell lysates overexpressing rat 5-LO. The leukotriene B4 (LTB4) level was assayed in rat basophilic leukemia (RBL-1) cell line. ICR (Institute of Cancer Research) mice were used for in vivo assays. Mouse ear edema was induced by topical application of arachidonic acid. An air pouch was induced by subcutaneous injection of sterile air into mice, followed by zymosan treatment. Sprague-Dawley rats were used for pharmacokinetic studies. Results: KRH-102140 inhibited 5-LO activity with an IC50 value of 160 ± 23 nmol/l in parallel with LTB4 inhibition in RBL-1 cells. Oral administration of KRH-102140 (10–100 mg/kg) reduced ear edema, myeloperoxidase activity and LTB4 production in murine inflammation models. Oral bioavailability as determined in rats was 66%. Conclusions: Our results show that KRH-102140, a new 5-LO inhibitor, exhibits potent anti-inflammatory activities in vitro as well as in vivo.

Synthesis and biological evaluation of thienopyrimidine derivatives as GPR119 agonists

A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R(1) and R(2) substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3 nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test.

Rosiglitazone reduces a wide range of proinflammatory profiles in synovial fibroblast SW982 under spheroid culture

Rosiglitazone (RSG) has been known to play a role in the modulation of inflammatory responses. Therefore, we sought to elucidate the underlying molecular mechanism by which RSG regulates the development of rheumatoid arthritis. Firstly, we examined the preventive effect of RSG on the inflammatory mediators induced by spheroid culture of synovial sarcoma SW982. Expression of proinflammatory cytokines under spheroid culture was more elevated than that under monolayer culture while RSG abolished inflammatory responses. The upregulation of inflammation-related genes by spheroid culture was closely associated with NFkappaB (NFkappaB) activation. Also, activation of p38 and c-Jun N-terminal kinase (JNK) by spheroid culture was abrogated with RSG treatment. Lastly, it was demonstrated that RSG reduced the development of arthritis in mice immunized with collagen, improving the histology of inflamed joint. In summary, RSG reduces inflammatory responses of synovial fibroblast via not only inhibition of NFkappaB but also modulation of both p38 and JNK.

Comparison of microstructure and strength in wire-drawn and rolled Cu-9 Fe-1.2 Ag filamentary microcomposite

Comparison of microstructure and strength of Cu-9 Fe-1.2 Ag microcomposite wires and sheets obtained by cold drawing or cold rolling combined with intermediate heat treatments has been made. The primary and secondary dendrite arms are aligned along the drawing or rolling direction and elongated into filaments after cold working. The microstructural scale of wire-drawn microcomposites was found to be finer than that of rolled microcomposites at the same drawing strain. The more effective microstructural refinement induced by unidirectional metallic flow and co-deformation of filament and Cu matrix resulted in finer microstructure in microcomposite wires. The ultimate tensile strength and the conductivity of wire-drawin Cu-Fe-Ag microcomposite were higher than those of rolled Cu-Fe-Ag microcomposites. The strength of Cu-Fe-Ag microcomposites is dependent on the spacing of the Fe filaments in accord with a Hall-Petch relationship. The good mechanical and electrical properties of wires may be associated with the more uniform distribution of fine filaments. The fracture surfaces of Cu-Fe-Ag wires and sheets showed ductile-type fracture and iron filaments were occasionally observed on the fracture surfaces. The fracture surface of Cu-Fe-Ag wires showed generally finer microstructural morphology than that of Cu-Fe-Ag sheets, consistent with the finer microstructural scale in Cu-Fe-Ag wires.

Protective effects of pyrrolidine dithiocarbamate against airway inflammation in the ovalbumin-induced mouse model.

Pyrrolidine dithiocarbamate (PDTC) is known to exert anti-tumor and anti-inflammatory effects. However, the effects of PDTC against airway inflammation and its underlying mechanisms have not been reported. In the present study, we examined the protective effects of PDTC in a murine model of asthma induced by ovalbumin. PDTC reduced the number of infiltrating inflammatory cells in concert with reduced eosinophil peroxidase (EPO) activity in bronchoalveolar lavage fluid. In parallel, PDTC decreased airway hyperresponsiveness in a dose dependent manner. All these effects were correlated with heme oxygenase-1 (HO-1) mRNA and protein induction, and reversed by ZnPP, a HO-1 inhibitor. In addition, PDTC reduced the secretion of Th(2) cytokines such as IL-4 and IL-5, whereas ZnPP blocked the inhibitory effects of PDTC on Th(2) cytokine secretion. These results suggest that PDTC protects against airway inflammation at least in part via HO-1 induction, and that inhibitory action on Th(2) cytokines may be associated with the protective mechanism of PDTC.

Determination of a peroxisome proliferator-activated receptor γ agonist, 1-(trans-methylimino-N-oxy)-6-(2-morpholinoethoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (KR-62980) in rat plasma by liquid chromatography-tandem mass spectrometry.

A novel peroxisome proliferator-activated receptor γ (PPARγ) agonist, KR-62980, was determined by liquid-liquid extraction with ethyl acetate and liquid chromatography-tandem mass spectrometry (LC/MS/MS) in rat plasma. In order to evaluate the pharmacokinetics of KR-62980, a reliable, selective and sensitive high-performance liquid chromatographic method with electrospray ionization tandem mass spectrometry was developed for the quantification of KR-62980 in rat plasma. KR-62980 and imipramine (IS) were separated on Hypersil GOLD C18 column with a mixture of acetonitrile-ammonium formate (10mM) (80:20, v/v) as mobile phase. The ion transitions monitored were m/z 437.2 → 114.2 for KR-62980, m/z 281.3 → 86.1 for imipramine in multiple reaction monitoring (MRM) mode. The percent recoveries of KR-62980 and imipramine were 90.1 and 98.4% from rat plasma, respectively. The linear dynamic range extended from 0.01 to 10 μg/ml with a correlation coefficient (R(2)) greater than 0.99 and the lower limit of quantification was 0.01 μg/ml. The mean of intra- and inter-assay precisions was 2.1 and 9.3%. The method was validated and successfully applied to the pharmacokinetic study of KR-62980 in rat.