苯并氧杂硼杂环磷酸二酯酶抑制剂治疗皮肤炎症：选择性，细胞活性以及对与皮肤炎症和皮肤结构变化相关的细胞因子的影响。,Journal of Pharmacology and Experimental Therapeutics

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苯并氧杂硼杂环磷酸二酯酶抑制剂治疗皮肤炎症：选择性，细胞活性以及对与皮肤炎症和皮肤结构变化相关的细胞因子的影响。
Journal of Pharmacology and Experimental Therapeutics ( IF 3.1 ) Pub Date : 2016-06-30 , DOI: 10.1124/jpet.116.232819
Chen Dong ₁ , Charlotte Virtucio ₂ , Olga Zemska ₂ , Grober Baltazar ₂ , Yasheen Zhou ₂ , Diogo Baia ₂ , Shannon Jones-Iatauro ₂ , Holly Sexton ₂ , Shamra Martin ₂ , Joshua Dee ₂ , Yvonne Mak ₂ , Maliwan Meewan ₂ , Fernando Rock ₂ , Tsutomu Akama ₂ , Kurt Jarnagin ₂

Affiliation

牛皮癣和特应性皮炎是影响数百万患者的皮肤疾病。在这里，我们表征苯并氧杂硼酸酯磷酸二酯酶（PDE）-4抑制剂，这是一类新的局部类药物，在2期或3期研究中已证明对牛皮癣和特应性皮炎具有治疗作用。Crisaborole [AN2728，4-（（（1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl）oxy]苄腈]，compd2 [2-乙氧基-6-（（1-羟基- 1,3-二氢苯并[c] [1,2] oxaborol-5-基）氧基）烟腈]，compd3 [6-（（1-羟基-1,3-二氢苯并[c] [1,2] oxaborol-5 -基）氧基）-2-（2-异丙氧基乙氧基）烟腈]和compd4 [5-氯-6-（（1-羟基-1,3-二氢苯并[c] [1,2]氧杂硼-5-基）氧基）-2-（（（4-氧戊基）氧基）烟腈]是有效的PDE4抑制剂，对PDE4同工型具有相似的亲和力，并且对催化域和全长酶具有同等的抑制作用。这些苯并氧杂硼烷对其他PDE同工酶的活性较低。Compd4与PDE4B2的催化结构域结合，其氧杂硼烷基与催化双金属螯合，并在底物水解过程中与cAMP中的磷酸盐重叠，并且相互作用扩展到腺嘌呤口袋中。在细胞培养中，苯并x硼烷PDE4抑制剂抑制肿瘤坏死因子-α，白介素（IL）-23，IL-17，干扰素-γ，IL-4，IL-5，IL-13和IL-22的释放，以及这些细胞因子导致皮肤结构和屏障功能的病理变化，以及特应性皮炎和牛皮癣的免疫失调。用compd3或N（6），2'-O-二丁酰腺苷3'，5'处理环一磷酸增加人单核细胞中cAMP反应元件结合蛋白的磷酸化，并减少人T细胞中细胞外信号调节的激酶磷酸化；这些变化导致细胞因子产生减少，并且是compd3阻止细胞因子释放的机制之一。局部compd3渗透皮肤并抑制佛波肉豆蔻酸酯乙酸酯诱导的IL-13，IL-22，IL-17F和IL-23转录，以及卡泊三醇诱导的小鼠胸腺基质淋巴细胞生成素表达。皮肤变薄是糖皮质激素的主要剂量限制副作用。相反，重复使用compd3不会使小鼠皮肤变薄。这些发现表明苯并氧杂硼烷PDE4抑制剂在治疗牛皮癣和特应性皮炎方面的潜在益处和安全性。这些变化导致细胞因子产生减少，并且是compd3阻止细胞因子释放的机制之一。局部compd3渗透皮肤并抑制佛波肉豆蔻酸酯乙酸酯诱导的IL-13，IL-22，IL-17F和IL-23转录，以及卡泊三醇诱导的小鼠胸腺基质淋巴细胞生成素表达。皮肤变薄是糖皮质激素的主要剂量限制副作用。相反，重复使用compd3不会使小鼠皮肤变薄。这些发现表明苯并氧杂硼烷PDE4抑制剂在治疗牛皮癣和特应性皮炎方面的潜在益处和安全性。这些变化导致细胞因子产生减少，并且是compd3阻止细胞因子释放的机制之一。局部compd3渗透皮肤并抑制佛波肉豆蔻酸酯乙酸酯诱导的IL-13，IL-22，IL-17F和IL-23转录，以及卡泊三醇诱导的小鼠胸腺基质淋巴细胞生成素表达。皮肤变薄是糖皮质激素的主要剂量限制副作用。相反，重复使用compd3不会使小鼠皮肤变薄。这些发现表明苯并氧杂硼烷PDE4抑制剂在治疗牛皮癣和特应性皮炎方面的潜在益处和安全性。IL-23转录和卡泊三醇诱导的小鼠胸腺基质淋巴细胞生成素表达。皮肤变薄是糖皮质激素的主要剂量限制副作用。相反，重复使用compd3不会使小鼠皮肤变薄。这些发现表明苯并氧杂硼烷PDE4抑制剂在治疗牛皮癣和特应性皮炎方面的潜在益处和安全性。IL-23转录和卡泊三醇诱导的小鼠胸腺基质淋巴细胞生成素表达。皮肤变薄是糖皮质激素的主要剂量限制副作用。相反，重复使用compd3不会使小鼠皮肤变薄。这些发现表明苯并氧杂硼烷PDE4抑制剂在治疗牛皮癣和特应性皮炎方面的潜在益处和安全性。

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Treatment of Skin Inflammation with Benzoxaborole Phosphodiesterase Inhibitors: Selectivity, Cellular Activity, and Effect on Cytokines Associated with Skin Inflammation and Skin Architecture Changes.

Psoriasis and atopic dermatitis are skin diseases affecting millions of patients. Here, we characterize benzoxaborole phosphodiesterase (PDE)-4 inhibitors, a new topical class that has demonstrated therapeutic benefit for psoriasis and atopic dermatitis in phase 2 or phase 3 studies. Crisaborole [AN2728, 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile], compd2 [2-ethoxy-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)nicotinonitrile], compd3 [6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-(2-isopropoxyethoxy)nicotinonitrile], and compd4 [5-chloro-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-((4-oxopentyl)oxy)nicotinonitrile] are potent PDE4 inhibitors with similar affinity for PDE4 isoforms and equivalent inhibition on the catalytic domain and the full-length enzyme. These benzoxaboroles are less active on other PDE isozymes. Compd4 binds to the catalytic domain of PDE4B2 with the oxaborole group chelating the catalytic bimetal and overlapping with the phosphate in cAMP during substrate hydrolysis, and the interaction extends into the adenine pocket. In cell culture, benzoxaborole PDE4 inhibitors suppress the release of tumor necrosis factor-α, interleukin (IL)-23, IL-17, interferon-γ, IL-4, IL-5, IL-13, and IL-22, and these cytokines contribute to the pathologic changes in skin structure and barrier functions as well as immune dysregulation in atopic dermatitis and psoriasis. Treatment with compd3 or N(6),2'-O-dibutyryladenosine 3',5'-cyclic monophosphate increases cAMP response element binding protein phosphorylation in human monocytes and decreases extracellular signal-regulated kinase phosphorylation in human T cells; these changes lead to reduced cytokine production and are among the mechanisms by which compd3 blocks cytokine release. Topical compd3 penetrates the skin and suppresses phorbol myristate acetate-induced IL-13, IL-22, IL-17F, and IL-23 transcription and calcipotriol-induced thymic stromal lymphopoietin expression in mouse skin. Skin thinning is a major dose-limiting side effect of glucocorticoids. By contrast, repeated application of compd3 did not thin mouse skin. These findings show the potential benefits and safety of benzoxaborole PDE4 inhibitors for the treatment of psoriasis and atopic dermatitis.

更新日期：2019-11-01

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