Synthesis and structure activity relationships of glycine amide derivatives as novel Vascular Adhesion Protein-1 inhibitors

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• 作者：Susumu Yamaki ; ^{susumu.yamaki@astellas.com} ; Daisuke Suzuki ; Jiro Fujiyasu ; Masahiro Neya^&dagger ; ; Akira Nagashima ; Mitsuhiro Kondo ; Takafumi Akabane ; Keitaro Kadono ; Ayako Moritomo ; Kosei Yoshihara^&Dagger ;
• 关键词：Vascular Adhesion Protein-1 ; Diabetic microvascular complication ; Glycine amide ; PAMPA
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：25
• 期：1
• 页码：187-201
• 全文大小：2977 K
• 卷排序：25

文摘

Vascular Adhesion Protein-1 (VAP-1) is a promising therapeutic target for the treatment of several inflammatory-related diseases including diabetic microvascular complication. We identified glycine amide derivative 3 as a novel structure with moderate VAP-1 inhibitory activity. Structure-activity relationship studies of glycine amide derivatives revealed that the tertiary amide moiety is important for stability in rat blood and that the position of substituents on the left phenyl ring plays an important role in VAP-1 inhibitory activity. We also found that low TPSA values and weak basicity are both important for high PAMPA values for glycine amide derivatives. These findings led to the identification of a series of orally active compounds with enhanced VAP-1 inhibitory activity. Of these compounds, 4g exhibited the most potent ex vivo efficacy, with plasma VAP-1 inhibitory activity of 60% after oral administration at 1 mg/kg.