|
Type |
Poster Presentation |
Area |
Medicinal Chemistry |
Room No. |
Exhibition Hall 2+3 |
Time |
10월 19일 (목요일) 11:00~12:30 |
Code |
MEDI.P-313 |
Subject |
Benzenesulfonyl Amide Derivatives as Selective mPGES-1 Inhibitors Ameliorate the Cognitive Impairment in Animal Model |
Authors |
Hui Rak Jeong, sunyoung Kim, Jae Yeol Lee* Department of Chemistry, Kyung Hee University, Korea |
Abstract |
A novel series of phenylsulfonyl hydrazide derivatives reduced LPS-induced PGE2 levels in RAW 264.7 macrophage cells via an inhibition of mPGES-1 enzyme. However, two regioisomers of phenylsulfonyl hydrazide exhibiting a wide range of biological activities were formed depending on the reaction conditions. In order to avoid this synthetic problem, new benzenesulfonyl amide (5: MPO-0112) as an analogue of potent phenylsulfonyl hydrazide (MPO-0063) was synthesized and biologically evaluated in vitro. As a result, MPO-0112 strongly suppressed LPS-induced PGE2 production (IC50: 0.34 μM) with excellent selectivity over COX-enzymes (COX-1 and 2) and also inhibited mPGES-1 enzyme (IC50: 7.37 μM) comparable to those of MPO-0063. According to the recent studies on the close correlation between up-regulation of mPGES-1 and Alzheimer's disease, we investigated whether MPO-0112 can ameliorate scopolamine-induced memory impairment using the passive avoidance test. The memory impairment-ameliorating effect of MPO-0112 (1.0 mg/kg, p.o.) was effective comparable to that of donepezil (5 mg/kg, p.o.) as a positive control. In addition, MPO-0112 exhibited a favorable in vitro CYP profile, which is suggestive of no potential drug–drug interactions. Therefore, these overall results suggest that MPO-0112 as selective mPGES-1 inhibitor may be a novel therapeutic agent for diseases associated with cognitive deficits, such as Alzheimer's disease. |
E-mail |
shi7747685@naver.com |
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