Inhibition of intracellular N-acylethanolamine-hydrolyzing acid amidase (NAAA) activity is a promising approach to manage the inflammatory response under disabling conditions. In fact, NAAA inhibition preserves endogenous palmitoylethanolamide (PEA) from degradation, thus increasing and prolonging its anti-inflammatory and analgesic efficacy at the inflamed site. In the present work, we report the identification of a potent, systemically available, novel class of NAAA inhibitors, featuring a pyrazole azabicyclo[3.2.1]octane structural core. After an initial screening campaign, a careful structure–activity relationship study led to the discovery of endo-ethoxymethyl-pyrazinyloxy-8-azabicyclo[3.2.1]octane-pyrazole sulfonamide 50 (ARN19689), which was found to inhibit human NAAA in the low nanomolar range (IC₅₀ = 0.042 μM) with a non-covalent mechanism of action. In light of its favorable biochemical, in vitro and in vivo drug-like profile, sulfonamide 50 could be regarded as a promising pharmacological tool to be further investigated in the field of inflammatory conditions.

中文翻译：

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吡唑氮杂双环 [3.2.1] 辛烷磺酰胺作为一类新型非共价 N-酰基乙醇胺水解酸酰胺酶 (NAAA) 抑制剂的发现和 SAR 进化，用于口服给药

抑制细胞内N-酰基乙醇胺水解酸酰胺酶 (NAAA) 活性是一种在致残条件下控制炎症反应的有前途的方法。事实上，NAAA 抑制可防止内源性棕榈酰乙醇酰胺 (PEA) 降解，从而增加和延长其在发炎部位的抗炎和镇痛功效。在目前的工作中，我们报告了一种有效的、系统可用的、新型 NAAA 抑制剂的鉴定，其特征是吡唑氮杂双环 [3.2.1] 辛烷结构核心。经过初步筛选活动，仔细的构效关系研究导致发现了内-乙氧基甲基-吡嗪氧基-8-氮杂双环[3.2.1]辛烷-吡唑磺酰胺50 ( ARN19689)，它被发现在低纳摩尔范围内抑制人类 NAAA (IC ₅₀ = 0.042 μM)，具有非共价作用机制。鉴于其良好的生化、体外和体内药物样特征，磺胺50可被视为一种有前途的药理学工具，有待在炎症领域进一步研究。