PXS-4681A，一种有效的基于选择性机制的SSAO / VAP-1抑制剂，在体内具有抗炎作用。,Journal of Pharmacology and Experimental Therapeutics

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PXS-4681A，一种有效的基于选择性机制的SSAO / VAP-1抑制剂，在体内具有抗炎作用。
Journal of Pharmacology and Experimental Therapeutics ( IF 3.1 ) Pub Date : 2013-08-15 , DOI: 10.1124/jpet.113.207613
Jonathan S Foot ₁ , Tin T Yow , Heidi Schilter , Alberto Buson , Mandar Deodhar , Alison D Findlay , Lily Guo , Ian A McDonald , Craig I Turner , Wenbin Zhou , Wolfgang Jarolimek

Affiliation

氨基脲敏感的胺氧化酶（SSAO），也称为血管粘附蛋白1（VAP-1），是铜依赖性胺氧化酶家族的成员，与各种形式的炎症和纤维化有关。为了研究SSAO / VAP-1抑制的治疗潜力，需要具有药物样特性的有效和选择性抑制剂。PXS-4681A [（Z）-4-（2-（氨基甲基）-3-氟代烯丙氧基）苯磺酰胺盐酸盐]是一种基于机理的酶功能抑制剂，具有药代动力学和药效学特性，可确保对酶的完全，长期抑制体内一次低剂量后。PXS-4681A不可逆地抑制了该酶，其表观Ki为37 nM，运动蛋白为0.26 min（-1），在体外未观察到周转。当针对相关的胺氧化酶，离子通道和七跨膜结构域受体进行分析时，它对SSAO / VAP-1具有高度选择性，并且优于先前报道的抑制剂。在肺部炎症和局部炎症的小鼠模型中，以2 mg / kg的剂量给药该分子可减轻中性粒细胞迁移，肿瘤坏死因子-α和白介素6的水平。这些结果证明了PXS-4681A的类药物特性及其在炎症治疗中的潜在用途。

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PXS-4681A, a potent and selective mechanism-based inhibitor of SSAO/VAP-1 with anti-inflammatory effects in vivo.

Semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1), is a member of the copper-dependent amine oxidase family that is associated with various forms of inflammation and fibrosis. To investigate the therapeutic potential of SSAO/VAP-1 inhibition, potent and selective inhibitors with drug-like properties are required. PXS-4681A [(Z)-4-(2-(aminomethyl)-3-fluoroallyloxy)benzenesulfonamide hydrochloride] is a mechanism-based inhibitor of enzyme function with a pharmacokinetic and pharmacodynamic profile that ensures complete, long-lasting inhibition of the enzyme after a single low dose in vivo. PXS-4681A irreversibly inhibits the enzyme with an apparent Ki of 37 nM and a kinact of 0.26 min(-1) with no observed turnover in vitro. It is highly selective for SSAO/VAP-1 when profiled against related amine oxidases, ion channels, and seven-transmembrane domain receptors, and is superior to previously reported inhibitors. In mouse models of lung inflammation and localized inflammation, dosing of this molecule at 2 mg/kg attenuates neutrophil migration, tumor necrosis factor-α, and interleukin-6 levels. These results demonstrate the drug-like properties of PXS-4681A and its potential use in the treatment of inflammation.

更新日期：2019-11-01

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