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.
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【Synthesis and structure-activity relationship of potent, selective and orally active anthranilamide-based factor Xa inhibitors: application of weakly basic sulfoximine group as novel S4 binding element.].
【强效、选择性和口服活性邻氨基苯甲酰胺类因子Xa抑制剂的合成及其构效关系: 弱碱性磺胺基作为新型S4结合元件的应用。】
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DOI：10.1016/j.ejmech.2012.10.005文章类型：杂志文章
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已经确定了一系列新型的有效且有效的Xa因子抑制剂，该抑制剂在邻氨基苯甲酰胺化学型中具有磺胺嘧啶部分作为新型的S4结合元件。在这种新型P4组中进行铅优化可导致许多有效的Xa因子抑制剂在人血浆中具有出色的抗凝活性。将选定的化合物口服给大鼠，并检查其离体凝血酶原时间延长活性，结果鉴定了化合物5-氯-N-(5-氯吡啶-2-基)-2-(4-(N-(2-二乙基氨基) 乙酰基)-S-甲基磺酰亚胺基) 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。该化合物18f及其活性代谢物18b在大鼠动脉和静脉血栓形成模型中均表现出出色的体内功效，并被发现对相关丝氨酸蛋白酶具有高度选择性。基于这一前景，选择化合物18f进行进一步评估。
