A novel series of potent and efficacious factor Xa inhibitors which possesses sulfoximine moiety as novel S4 binding element in anthranilamide chemotype has been identified. Lead optimization at this novel P4 group led to many potent factor Xa inhibitors with excellent anticoagulant activity in human plasma. Selected compounds were dosed orally in rats and checked for their ex vivo prothrombin time prolonging activity, which resulted in identification of compound 5-chloro-N-(5-chloropyridin-2-yl)-2-(4-(N-(2-(diethylamino)acetyl)-S-methylsulfonimidoyl)benzamido)benzamide (18f). The detailed pharmacokinetic evaluation and subsequent metabolism study of 18f suggested the presence of an active metabolite. The compound 18f and its active metabolite 18b demonstrated excellent in vivo efficacy in both arterial and venous thrombosis model in rats and were found to be highly selective against related serine proteases. Based on this promising profile, compound 18f was selected for further evaluation.

译文

:已经鉴定了一系列有效且有效的因子Xa抑制剂,其具有硫肟亚胺部分作为邻氨基苯甲酰胺化学型中的新的S4结合元件。在这个新颖的P4组中的前导优化导致了许多有效的Xa抑制剂在人血浆中具有出色的抗凝活性。在大鼠中口服选择的化合物并检查其离体凝血酶原时间延长活性,从而鉴定出化合物5-氯-N-(5-氯吡啶-2-基)-2-(4-(N-(2 -(二乙氨基)乙酰基)-S-甲基磺酰亚胺基)苯甲酰胺基)苯甲酰胺(18f)。 18f的详细药代动力学评估和随后的代谢研究表明存在活性代谢物。化合物18f及其活性代谢物18b在大鼠的动脉和静脉血栓形成模型中均显示出优异的体内功效,并且被发现对相关的丝氨酸蛋白酶具有高度选择性。基于这一有前途的概况,选择了化合物18f进行进一步评估。

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