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Park J.-H.,Gwangju Institute of Science and Technology | Lee G.-E.,Korea Health Industry Development Institute KHIDI | Lee S.-D.,Gwangju Institute of Science and Technology | Hien T.T.,Chosun University | And 8 more authors.
Journal of Medicinal Chemistry | Year: 2015

Novel 2,5-dioxoimidazolidine-based conformationally constrained analogues of KN62 (1) were developed as P2X7 receptor (P2X7R) antagonists using a rigidification strategy of the tyrosine backbone of 1. SAR analysis of the 2,5-dioxoimidazolidine scaffold indicated that piperidine substitution at the N3 position and no substitution at N1 position were preferable. Further optimization of the substituents at the piperidine nitrogen and the spacer around the skeleton resulted in several superior antagonists to 1, including 1-adamantanecarbonyl analogue 21i (IC50 = 23 nM in ethidium uptake assay; IC50 = 14 nM in IL-1β ELISA assay) and (3-CF3-4-Cl)benzoyl analogue (-)-21w (54 nM in ethidium uptake assay; 9 nM in IL-1β ELISA assay), which was more potent than the corresponding (+) isomer. Compound 21w displayed potent inhibitory activity in an ex vivo model of LTP-induced pain signaling in the spinal cord and significant anti-inflammatory activity in in vivo models of carrageenan-induced paw edema and type II collagen-induced joint arthritis. © 2015 American Chemical Society. Source


Yea C.-H.,Sogang University | Yea C.-H.,Korea Health Industry Development Institute KHIDI | Jeong H.-C.,Sogang University | Moon S.-H.,Konkuk University | And 4 more authors.
Biomaterials | Year: 2016

Conventional methods for quantification of undifferentiated pluripotent stem cells such as fluorescence-activated cell sorting and real-time PCR analysis have technical limitations in terms of their sensitivity and recyclability. Herein, we designed a real-time in situ label-free monitoring system on the basis of a specific electrochemical signature of human pluripotent stem cells in vitro. The intensity of the signal of hPSCs highly corresponded to the cell number and remained consistent in a mixed population with differentiated cells. The electrical charge used for monitoring did not markedly affect the proliferation rate or molecular characteristics of differentiated human aortic smooth muscle cells. After YM155 treatment to ablate undifferentiated hPSCs, their specific signal was significantly reduced. This suggests that detection of the specific electrochemical signature of hPSCs would be a valid approach to monitor potential contamination of undifferentiated hPSCs, which can assess the risk of teratoma formation efficiently and economically. © 2015 Elsevier Ltd. Source


Park J.-H.,Gwangju Institute of Science and Technology | Lee G.-E.,Korea Health Industry Development Institute KHIDI | Lee S.-D.,Gwangju Institute of Science and Technology | Ko H.,Gwangju Institute of Science and Technology | Kim Y.-C.,Gwangju Institute of Science and Technology
European Journal of Medicinal Chemistry | Year: 2015

As an optimization strategy, the flexible structure of KN-62, a known P2X7 receptor antagonist, was converted into conformationally constrained derivatives using pyrimidine-2,4-dione as the core skeleton. Various modifications at the 4-position of the piperazine moiety of the new lead compound were performed to improve P2X7 receptor antagonistic activities, which were evaluated in HEK293 cells stably expressing the human P2X7 receptor (EtBr uptake assay) and in THP-1 cells (IL-1β ELISA assay). According to the results, polycycloalkyl acyl or di-halogenated benzoyl substituents were much more favorable than the original phenyl group of KN-62. Among these compounds, the trifluoromethyl-chloro benzoyl derivative 18m and adamantyl carbonyl derivatives 19g-19i and 19k showed potent antagonistic effects, with IC50 values ranging from 10 to 30 nM. In addition, the in vitro adsorption, distribution, metabolism, excretion, and toxicity (ADMET) profile of 18m was determined to be in acceptable ranges in terms of metabolic stability and cytotoxicity. These results suggest that pyrimidine-2,4-dione derivatives may be promising novel P2X7 receptor antagonists for the development of anti-inflammatory drugs. © 2015 Published by Elsevier Masson SAS. Source


Park J.-H.,Kyung Hee University | Youm S.,Dongguk University | Jeon Y.,Korea Health Industry Development Institute KHIDI | Park S.-H.,Kyung Hee University
International Journal of Industrial Ergonomics | Year: 2015

The purpose of this research is to develop a postural balance evaluation system using center-of-pressure (COP) analysis techniques for early diagnosis of Parkinson's disease (PD). A COP sensing device was developed, and applicable test protocols were proposed. Subsequently, posturographic parameters, which reflect the characteristics of postural control, were extracted to evaluate postural balance. Decisive indicators for postural stability were selected among the posturographic parameters through statistical validation based on clinical data. A discriminant function was then suggested to predict the existence of PD in patients. This clinical study consisted of 127 participating subjects. A validation study (n = 51, 40% of the overall data) using the discriminant function concluded with 100% accuracy that 37 healthy subjects did not have PD and 14 subjects with PD were correctly diagnosed. Relevance to industry: Postural instability has become a critical issue since people with postural balance disorders are frequently exposed to the danger of falling and injuries. This paper provides a device, test protocol, and evaluation method to analyze postural balance and predict the existence of PD. We expect that our proposed system can be exploited for neurosurgery of PD patients, and other clinical medical fields such as rehabilitation, geriatrics, and orthopedics. © 2015 Elsevier B.V. Source


Patent
Korea Health Industry Development Institute Khidi and Konkuk University | Date: 2012-02-16

The present invention relates to a novel compound isolated from

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