Pyrazole-based arylalkyne cathepsin S inhibitors. Part II: Optimization of cellular potency

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• 作者：Michael K. Ameriks ; Hui Cai ; James P. Edwards ; Damara Gebauer ; Elizabeth Gleason ; Yin Gu ; Lars Karlsson ; Steven Nguyen ; Siquan Sun ; Robin L. Thurmond ; Jian Zhu
• 关键词：Cathepsin ; Protease ; Invariant chain ; Lysosomotropism
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：1 November 2009
• 年：2009
• 卷：19
• 期：21
• 页码：6135-6139
• 全文大小：342 K

文摘

Basic lipophilic substituents dramatically improved the cellular potency of a previously disclosed series of pyrazole-based arylalkyne cathepsin S inhibitors. The incorporation of substituted benzylamines in the para position of the arylalkyne maintained enzymatic activity (hCatS IC₅₀ = 80–420 nM) and imparted cellular potency (IC₅₀ = 0.8–4.0 μM). Further refinement of the morpholine portion of the pharmacophore enabled the identification of bicyclic piperidines with enhanced affinity for CatS (IC₅₀ = 10–30 nM) and sub-micromolar cellular potency (JY Ii IC₅₀ = 200–720 nM).