Hoh-Gyu Hahn

Effects of N-adamantyl-4-methylthiazol-2-amine on hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic rats.

Thiazole derivatives are attractive candidates for drug development because they can be efficiently synthesized and are active against a number of diseases and conditions, including diabetes. In our present study, we investigated the anti-inflammatory and antioxidant properties of N-adamantyl-4-methylthiazol-2-amine (KHG26693), a new thiazole derivative, in a streptozotocin (STZ)-induced model of diabetes mellitus. STZ-induced diabetic rats were intraperitoneally administered KHG26693 (3mg/kg-body weight/day) for 4 weeks. KHG26693 administration significantly decreased blood glucose, triglycerides, and cholesterol and increased insulin. KHG26693 also suppressed several inflammatory responses in STZ-induced diabetic rats, as evidenced by decreased levels of serum tumor necrosis factor-α, interleukin-1β, and nitric oxide. Additionally, KHG26693 significantly modulated hepatic lipid peroxidation, catalase and superoxide dismutase activity, and the nonenzymatic antioxidant status (e.g., vitamins C and E), and reduced the glutathione content. These anti-inflammatory/antioxidative actions occurred as a result of the downregulation of inducible nitric oxide synthase and nuclear factor-kappa B. Taken together, our results suggest that KHG26693 successfully reduces the production of oxidative stress in STZ-induced diabetic rats by regulating the oxidation-reduction system, specifically increasing antioxidant capacity. Furthermore, KHG26693 treatment significantly reverted the key enzymes of glucose metabolism, such as glucokinase, glucose-6-phosphatase, glycogen synthase, glycogen phosphorylase, and fructose-1,6-bisphosphatase, to near-normal levels in liver tissues. These results indicate that KHG26693 normalizes disturbed glucose metabolism by enhancing glucose utilization and decreasing liver glucose production via insulin release, suggesting the possibility of future diabetes treatments.

Anti-oxidative and anti-inflammatory effects of 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride on glutamate-induced neurotoxicity in rat brain.

In a previous in vitro study, we demonstrated the protective effects of a new drug, 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride (KHG26377), against glutamate-induced excitotoxicity in cultured glial cells. In this study, we explored the possible mechanisms underlying the neuroprotective and anti-inflammatory effects of this compound against glutamate-induced excitotoxicity in rat brain. Our results showed that pretreatment with KHG26377 significantly attenuated glutamate-induced elevation of lipid peroxidation, TNF-α, IFN-γ, nitric oxide, reactive oxygen species, NADPH oxidase, and Ca(2+) levels, as well as the expression of caspase-3, neuronal nitric oxide synthase, and pERK. Furthermore, KHG26377 pretreatment attenuated key antioxidant parameters such as levels of superoxide dismutase, catalase, glutathione, glutathione peroxidase, and glutathione reductase, and also mitigated suppression of mitochondrial transmembrane potential by glutamate toxicity. Thus, through its antioxidant and anti-inflammatory activities in rat brain, KHG26377 may help protect against glutamate-induced neuronal damage.

Pharmacokinetics of propentofylline and the quantitation of its metabolite hydroxypropentofylline in human volunteers

Propentofylline (PPF, 3-methyl-1-(5-oxohexyl)-7-propylxanthine) has been reported to be effective for the treatment of both vascular dementia and dementia of the Alzheimer type. The pharmacological effects of PPF may be exerted via the stimulation of nerve growth factor, increased cerebral blood flow, and inhibition of adenosine uptake. The objectives of this experiment are to determine the kinetic behavior of PPF, to identify, and to quantify its metabolite in human. Blood samples were obtained from human volunteers following oral administration of 200 mg of PPF tablets. For the identification and quantification of the metabolite, 3-methyl-1-(5-hydroxyhexyl)-7-propylxanthine (PPFOH), PPFOH was synthesized and identified by gas chromatography/mass spectroscopy (GC/MS) and1H-nuclear magnetic resonance spectroscopy. The molecular weight of synthesized metabolite is 308 dalton. The PPF and PPFOH in plasma were extracted with diethyl ether and identified by electron impact GC/MS. The plasma concentrations of PPF and PPFOH were determined by gas chromatography/nitrogen phosphorus detector in plasma and their pharmacokinetic parameters were determined. The mean half-life of PPF was 0.74 hr. The areas under the curve (AUCs) of PPF and PPFOH were 508 and 460 ng.hr/ml, respectively. Cmax of PPF was about 828.4 ng/ml and the peak concentration was achieved at about 2.2 hr (Tmax). These results indicate that PPF is rapidly disappeared from blood due to extensive metabolism into PPFOH.

Design and Synthesis of Novel Antidiabetic Agents

The synthesis and structure-activity relationships of a novel series of substituted quercetins that activates peroxisome proliferator-activated receptor gamma (PPARγ) are reported. The PPARγ agonistic activity of the most potent compound in this series is comparable to that of the thiazolidinedione-based antidiabetic drugs currently in clinical use.

The azetidine derivative, KHG26792 protects against ATP-induced activation of NFAT and MAPK pathways through P2X7 receptor in microglia.

Azetidine derivatives are of interest for drug development because they may be useful therapeutic agents. However, their mechanisms of action remain to be completely elucidated. Here, we have investigated the effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) on ATP-induced activation of NFAT and MAPK through P2X7 receptor in the BV-2 mouse microglial cell line. KHG26792 decreased ATP-induced TNF-α release from BV-2 microglia by suppressing, at least partly, P2X7 receptor stimulation. KHG26792 also inhibited the ATP-induced increase in IL-6, PGE2, NO, ROS, CXCL2, and CCL3. ATP induced NFAT activation through P2X7 receptor, with KHG26792 reducing the ATP-induced NFAT activation. KHG26792 inhibited an ATP-induced increase in iNOS protein and ERK phosphorylation. KHG26792 prevented an ATP-induced increase in MMP-9 activity through the P2X7 receptor as a result of degradation of TIMP-1 by cathepsin B. Our data provide mechanistic insights into the role of KHG26792 in the inhibition of TNF-α produced via P2X7 receptor-mediated activation of NFAT and MAPK pathways in ATP-treated BV-2 cells. This study highlights the potential use of KHG26792 as a therapeutic agent for the many diseases of the CNS related to activated microglia.

KHG26792 Inhibits Melanin Synthesis in Mel-Ab Cells and a Skin Equivalent Model

The purpose of this study is to characterize the effects of KHG26792 (3-(naphthalen-2-yl(propoxy) methyl)azetidine hydrochloride), a potential skin whitening agent, on melanin synthesis and identify the underlying mechanism of action. Our data showed that KHG26792 significantly reduced melanin synthesis in a dose-dependent manner. Additionally, KHG26792 downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase, the rate-limiting enzyme in melanogenesis, although tyrosinase was not inhibited directly. KHG26792 activated extracellular signal-regulated kinase (ERK), whereas an ERK pathway inhibitor, PD98059, rescued KHG26792-induced hypopigmentation. These results suggest that KHG26792 decreases melanin production via ERK activation. Moreover, the hypopigmentary effects of KHG26792 were confirmed in a pigmented skin equivalent model using Cervi cornus Colla (deer antler glue), in which the color of the pigmented artificial skin became lighter after treatment with KHG26792. In summary, our findings suggest that KHG26792 is a novel skin whitening agent.

A derivative of 2‐aminothiazole inhibits melanogenesis in B16 mouse melanoma cells via glycogen synthase kinase 3β phosphorylation

Objectives  We have investigated whether KHG25855 (2‐cyclohexylamino‐1,3‐thiazole hydrochloride) affected melanogenesis in B16 mouse melanoma cells, and the mechanisms involved.

Evaluation of substituted triazol-1-yl-pyrimidines as inhibitors of Bacillus anthracis acetohydroxyacid synthase.

Acetohydroxyacid synthase (AHAS), a potential target for antimicrobial agents, catalyzes the first common step in the biosynthesis of the branched-chain amino acids. The genes of both catalytic and regulatory subunits of AHAS from Bacillus anthracis (Bantx), a causative agent of anthrax, were cloned, overexpressed in Escherichia coli, and purified to homogeneity. To develop novel anti-anthracis drugs that inhibit AHAS, a chemical library was screened, and four chemicals, AVS2087, AVS2093, AVS2387, and AVS2236, were identified as potent inhibitors of catalytic subunit with IC(50) values of 1.0 +/- 0.02, 1.0 +/- 0.04, 2.1 +/- 0.12, and 2.0 +/- 0.08 microM, respectively. Further, these four chemicals also showed strong inhibition against reconstituted AHAS with IC(50) values of 0.05 +/- 0.002, 0.153 +/- 0.004, 1.30 +/- 0.10, and 1.29 +/- 0.40 microM, respectively. The basic scaffold of the AVS group consists of 1-pyrimidine-2-yl-1H-[1,2,4]triazole-3-sulfonamide. The potent inhibitor, AVS2093 showed the lowest binding energy, -8.52 kcal/mol and formed a single hydrogen bond with a distance of 1.973 A. As the need for novel antibiotic classes to combat bacterial drug resistance increases, the screening of new compounds that act against Bantx-AHAS shows that AHAS is a good target for new anti-anthracis drugs.

Neuroprotective effects of N-adamantyl-4-methylthiazol-2-amine against amyloid β-induced oxidative stress in mouse hippocampus

We previously reported that N-adamantyl-4-methylthiazol-2-amine (KHG26693) suppresses amyloid beta (Aβ)-induced neuronal oxidative damage in cortical neurons. Here we investigated the mechanism and antioxidative function of KHG26693 in the hippocampus of Aβ-treated mice. KHG26693 significantly attenuated Aβ-induced TNF-α and IL-1β enhancements. KHG26693 decreased Aβ-mediated malondialdehyde formation, protein oxidation, and reactive oxygen species by decreasing the iNOS level. KHG26693 suppressed Aβ-induced oxidative stress through a mechanism involving glutathione peroxidase, catalase, and GSH attenuation. Aβ-induced MMP-2, cPLA2, and pcPLA2 expressions were almost completely attenuated by KHG26693 treatment, suggesting that Aβ-induced oxidative stress reduction by KHG26693 is, at least partly, caused by the downregulation of MMP-2 and cPLA2 activation. Compared with Aβ treatment, KHG26693 treatment upregulated Nrf2 and HO-1 expressions, suggesting that KHG26693 protects the brain from Aβ-induced oxidative damage, likely by maintaining redox balance through Nrf2/HO-1 pathway regulation. KHG26693 significantly attenuated Aβ-induced oxidative stress in the hippocampus of Aβ-treated mice.

Suppression of lipopolysaccharide-induced microglial activation by a benzothiazole derivative

We previously reported that KHG21834, a benzothiazole derivative, attenuates the beta-amyloid (Aβ)-induced degeneration of both cortical and mesencephalic neurons in vitro. Central nervous system inflammation mediated by activated microglia is a key event in the development of neurodegenerative disease. In this study, we show that KHG21834 suppresses inflammation-mediated cytokine upregulation. Specifically, KHG21834 induces significant reductions in the lipopolysaccharide-induced activation of microglia and production of proinflammatory mediators such as tumor necrosis factor-α, interlukin-1β, nitric oxide, and inducible nitric oxide synthase. In addition, KHG21834 blocks the expression of mitogen-activated protein kinases, including ERK, p38 MAPK, JNK, and Akt. In vivo intracerebroventricular infusion of KHG21834 also leads to decreases the level of interleukin-1β and tumor necrosis factor-α in brain. These results, in combination with our previous findings on Aβ-induced degeneration, support the potential therapeutic efficacy of KHG21834 for the treatment of neurodegenerative disorders via the targeting of key glial activation pathways.