化学
活性代谢物
苯甲酰胺
体内
药理学
代谢物
铅化合物
部分
立体化学
离体
药代动力学
丝氨酸
口服活性
结构-活动关系
酶抑制剂
酶
生物化学
体外
生物技术
生物
医学
作者
Vrajesh B. Pandya,Mukul Jain,Ganes Chakrabarti,Hitesh Soni,Bhavesh Parmar,Balaji Chaugule,Jigar S. Patel,Tushar Jarag,Jignesh K. Joshi,Nirav Joshi,Akshyaya Rath,Vishal Unadkat,Bhavesh Sharma,Haresh Ajani,Jeevan Kumar,Kalapatapu V.V.M. Sairam,Harilal Patel,Pankaj Patel
标识
DOI:10.1016/j.ejmech.2012.10.005
摘要
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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