Hyeongjin Cho

Novel thiazolidinedione derivatives with anti-obesity effects: Dual action as PTP1B inhibitors and PPAR-γ activators

Benzylidene-2,4-thiazolidinedione derivatives with substitutions at both the ortho and para-positions of the phenyl group were synthesized as PTP1B inhibitors with IC(50) values in a low micromolar range. Compound 18l, the lowest, bore an IC(50) of 1.3 μM. In a peroxisome proliferator-activated receptor-γ (PPAR-γ) promoter reporter gene assay, 18l was found to activate the transcription of the reporter gene with potencies comparable to those of troglitazone, rosiglitazone, and pioglitazone. In vivo efficacy of 18l as an anti-obesity and hypoglycemic agent was evaluated in a mouse model system. Compound 18l significantly suppressed weight gain and significantly improved blood parameters such as TG, total cholesterol and NEFA without overt toxic effects.

Formylchromone derivatives as a novel class of protein tyrosine phosphatase 1B inhibitors

Formylchromone inhibits a human protein tyrosine phosphatase PTP1B with a IC(50) value of 73 microM. The chemical reactivity of formylchromone was adjusted by substitution at various positions of the formylchromone skeleton. In an initial assessment of the structure-activity relationship, the most potent inhibitor showed an IC(50) of 4.3 microM against PTP1B and strong or medium selectivity against other human PTPases, LAR and TC-PTP. This compound, however, was not selective against microbial PTPases, YPTP1 and YOP. The potency and selectivity of the formylchromone derivatives expecting further improvements provides a novel pharmacophore for the design of drugs for the treatment of type 2 diabetes and obesity.

Thiazolidinedione derivatives as PTP1B inhibitors with antihyperglycemic and antiobesity effects.

Benzylidene-2,4-thiazolidinedione derivatives with substitutions on the phenyl ring at the ortho or para positions of the thiazolidinedione (TZD) group were synthesized as PTP1B inhibitors with IC50 values in a low micromolar range. Compound 3e, the lowest, bore an IC50 of 5.0 microM. In vivo efficacy of 3e as an antiobesity and hypoglycemic agent was evaluated in a mouse model system. Significant improvement of glucose tolerance was observed. This compound also significantly suppressed weight gain and significantly improved blood parameters such as TG, total cholesterol and NEFA. Compound 3e was also found to activate peroxisome proliferator-activated receptors (PPARs) indicating multiple mechanisms of action.

Structure-based virtual screening approach to identify novel classes of PTP1B inhibitors.

Discovery of protein tyrosine phosphatase 1B (PTP1B) inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of type 2 diabetes and obesity. We have been able to identify 9 novel PTP1B inhibitors by means of a computer-aided drug design protocol involving virtual screening with docking simulations under consideration of the effects of ligand solvation in the binding free energy function. Because the newly discovered inhibitors are structurally diverse and reveal a significant potency with IC(50) values lower than 50 microM, all of them can be considered for further development by structure-activity relationship studies. Structural features relevant to the interactions of the newly identified inhibitors with the active-site residues of PTP1B are discussed in detail.

Protein tyrosine phosphatase 1B (PTP1B) and obesity.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the leptin and insulin signaling pathways. The important roles of PTP1B related to obesity and diabetes were confirmed by a deletion of PTP1B gene in mice. Mice with the whole body deletion of PTP1B were protected against the development of obesity and diabetes. When PTP1B gene was deleted selectively in the brain of mice, the major effects on weight and glucose control were consistent with the whole body deletion of PTP1B. This is in contrast to the muscle-, liver-, and adipocyte-specific deletion, which had no beneficial effects on obesity. While these results indicate the importance of neuronal PTP1B in maintaining energy homeostasis, the peripheral PTP1B is also being investigated for their potential roles in the control of energy balance. Validation of PTP1B as a therapeutic target for obesity and diabetes prompted efforts to develop potent and selective inhibitors of PTP1B. Among the small molecule inhibitors investigated, trodusquemine, which acts both centrally and peripherally, is currently in phase 2 clinical trials. An approach using PTP1B-directed antisense oligonucleotides is also in phase 2 clinical trials.

Design and synthesis of novel antimicrobial peptides on the basis of α helical domain of Tenecin 1, an insect defensin protein, and structure–activity relationship study

Abstract Tenecin 1, a peptide consisting of 43 amino acids, exhibits a potent bactericidal activity against various Gram-positive bacteria and shares a common structural feature of insect defensin family corresponding to cysteine stabilized α/β motif. Our previous research indicated that an active fragment was successfully extracted from C-terminal β sheet domain of Tenecin 1, whereas the fragment corresponding to the α helical region of the protein had no antibacterial activity. We chose this inactive fragment corresponding to α helical region of Tenecin 1 and synthesized derivatives with a different net positive charge by using rational design. Interestingly, we successfully endowed antibacterial activity as well as antifungal activity to the inactive α helical fragment by single or double amino acid replacement(s) without an increase of hemolytic activity. The leakage of dye from vesicles induced by the active peptides suggested that these peptides act on the membranes of pathogen as a primary mode of action. Structure–activity relationship study of a series of the active derivatives revealed that amphiphilic structure and high net positive charge were prerequisite factors for the activity and that there was a relationship between the antibacterial activity and the isoelectric point of the active peptides. In this work, we showed an efficient method to endow the antibacterial activity as well as antifungal activity to the inactive fragment derived from a cyclic insect defensin protein and suggested a facile method to screen for active fragments from cyclic host defense peptides.

Isoxazol‐5(4H)one Derivatives as PTP1B Inhibitors Showing an Anti‐Obesity Effect

In developing inhibitors of therapeutic target enzymes, significant time and effort are committed to the preparation of large numbers of compounds. In an effort to develop a potent inhibitor of protein tyrosine phosphatase (PTP) 1B as an anti-obesity and/or anti-diabetic agent, we constructed an isoxazolone chemical library by using a simplified procedure that circumvents tedious workup and purification steps. The 10×7 isoxazolone derivatives were synthesized by coupling the two halves of the target compounds. When mixed and heated in test tubes, the precursors produced the reaction products as precipitates. After brief washing, the products were pure enough to be used for enzymatic experiments. With the precursors for the coupling reactions prepared, the 10×7 library compounds could be prepared in a day by using the present protocol. The library compounds thus obtained were examined for their inhibitory activities against PTP1B. Among them, compound C3 was the most potent inhibitor of PTP1B with an IC(50) of 2.3 μM. The in vivo effect of C3 was also examined in an obesity-prone mouse strain. Diet-induced obese (DIO)/diabetic mice were divided into two groups and each group was fed a high-fat diet (HFD) or HFD+C3 for four weeks. The group of C3-fed mice gained significantly less weight relative to the HFD-fed control group during the four weeks of the drug feeding period. In contrast to the anti-obesity effect of C3, no difference was observed in the glycemic control of the HFD and HFD+C3 mice groups.

Indolicidin-derived antimicrobial peptide analogs with greater bacterial selectivity and requirements for antibacterial and hemolytic activities

Indolicidin (ILPWKWPWWPWRR-NH(2)) has received attention due to its unique primary structure and biological activities. In this study, amide bonds at various positions in indolicidin were replaced with the reduced amide bonds psi[CH(2)NH] and the effect of the secondary structure on the biological activity was investigated. The circular dichroism spectra revealed that the rigidity and hydrogen bond of the amide bond between Trp(8) and Trp(9) were important for stabilizing the turn structure of indolicidin. A structure-activity study revealed that the turn structure of indolicidin was not required for antimicrobial activity and leakage activity for LUVs with a negatively charged surface. The pseudopeptide containing two reduced amide bonds showed less hemolytic activity as well as improved stability without a decrease in its antimicrobial activity. These results will provide valuable information for designing indolicidin analogs with greater bacterial selectivity and increased stability and for elucidating the role of the secondary structure of membrane-active peptides for antimicrobial and hemolytic activities.

Inhibition of IKK-β: a new development in the mechanism of the anti-obesity effects of PTP1B inhibitors SA18 and SA32.

In a previous study, protein tyrosine phosphatase 1B (PTP1B) inhibitors, SA18 and SA32, exhibited anti-obesity effects in a mouse model by suppressing weight gain and improving blood parameters, including free fatty acid (FFA) levels. In a separate study, depletion of the PTP1B gene in mice suppressed weight gain without significant change in FFA levels. The discrepancy in FFA concentrations between the two studies suggested that the in vivo target of the SA compounds might not be limited to PTP1B. In this study, SA18 and SA32 were found to be potent inhibitors of IkappaB Kinase-beta (IKK-beta). In vivo relevance of the inhibitory activity was evaluated in differentiated adipocytes. Inhibition of IKK-beta, in addition to inhibition of PTP1B, in mice treated with the SA compounds, could be a possible mechanism of the compounds biological response including the resistance to diet-induced weight gain and improvement in blood parameters. As potent and cell-permeable IKK-beta inhibitors, SA18 and SA32 could also be valuable in biological experiments.

Derivatives of 1,4-bis(3-hydroxycarbonyl-4-hydroxyl)styrylbenzene as PTP1B inhibitors with hypoglycemic activity

Disalicylic acid derivatives with stilbene and bis-styrylbenzene skeleton were synthesized as PTP1B inhibitors. The most potent in this series exhibited a submicromolar IC(50) value. One of the compounds 7b was tested in an animal model for its efficacy as an anti-diabetic or an anti-obesity agent. In feeding compound 7b to diet-induced obese mice, no significant differences in weight gain and food consumption were observed between the drug-treated and the obese control mice. However, 7b significantly lowered the fasting glucose level and improved the glucose tolerance in the obesity-induced diabetic mice.