Synthesis and pharmacological characterization of benzenesulfonamides as dual species inhibitors of human and murine mPGES-1

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• 作者：Thomas Hanke ; Florian R枚rsch ; Theresa M. Thieme ; Nerea Ferreiros ; Gisbert Schneider ; Gerd Geisslinger ; Ewgenij Proschak ; Sabine Gr枚sch ; Manfred Schubert-Zsilavecz
• 关键词：Human mPGES-1 ; Murine mPGES-1 ; Sulfonamides ; SAR ; Inflammation ; Inhibitors
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：15 December, 2013
• 年：2013
• 卷：21
• 期：24
• 页码：7874-7883
• 全文大小：5824 K

文摘

The microsomal prostaglandin E₂ synthase 1 (mPGES-1) became a desirable target in recent years for the research of new anti-inflammatory drugs. Even though many potent inhibitors of human mPGES-1, tested in vitro assay systems, have been synthesized, they all failed in preclinical trials in rodent models of inflammation, due to the lack of activity on rodent enzyme. Within this work we want to present a new class of mPGES-1 inhibitors derived from a benzenesulfonamide scaffold with inhibitory potency on human and murine mPGES-1. Starting point with an IC₅₀ of 13.8 渭M on human mPGES-1 was compound 1 (4-{benzyl[(4-methoxyphenyl)methyl]sulfamoyl}benzoic acid; FR4), which was discovered by a virtual screening approach. Optimization during a structure-activity relationship (SAR) process leads to compound 28 (4-[(cyclohexylmethyl)[(4-phenylphenyl)methyl]sulfamoyl]benzoic acid) with an improved IC₅₀ of 0.8 渭M on human mPGES-1. For the most promising compounds a broad pharmacological characterization has been carried out to estimate their anti-inflammatory potential.