Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of PGE₂ production: Synthesis, biological activity, and molecular docking study

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• 作者：Minju Kim^a ; ^&dagger ; ; Sunhoe Lee^a ; ^&dagger ; ; Eun Beul Park^a ; Kwang Jong Kim^a ; Hwi Ho Lee^b ; Ji-Sun Shin^c ; Katrin Fischer^d ; Andreas Koeberle^d ; Oliver Werz^d ; ^{oliver.werz@uni-jena.de" class="auth_mail" title="E-mail the corresponding author} ; Kyung-Tae Lee^b ; ^{ktlee@khu.ac.kr" class="auth_mail" title="E-mail the corresponding author} ; Jae Yeol Lee^a ; ^{ljy@khu.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Inflammation ; Prostaglandin E2 ; Phenylsulfonyl hydrazide ; mPGES-1 ; Molecular docking study
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 January 2016
• 年：2016
• 卷：26
• 期：1
• 页码：94-99
• 全文大小：1009 K

文摘

Preliminary hit-to-lead optimization of a novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high throughput screening hit compound class="boldFont">1 (IC₅₀ = 5700 nM against PGE₂ production), for a potent suppressor of PGE₂ production is described. Subsequent optimization led to the identification of the potent lead compound class="boldFont">8n with IC₅₀ values of 4.5 and 6.9 nM, respectively, against LPS-induced PGE₂ production and NO production in RAW 264.7 macrophage cells. In addition, class="boldFont">8n was about 30- and >150-fold more potent against mPGES-1 enzyme in a cell-free assay (IC₅₀ = 70 nM) than MK-886 and hit compound class="boldFont">1, respectively. Molecular docking suggests that compound class="boldFont">8n could inhibit PGE₂ production by blocking the PGH₂ binding site of human mPGES-1 enzyme.