Synthesis and structure activity relationships of carbamimidoylcarbamate derivatives as novel vascular adhesion protein-1 inhibitors

Susumu Yamaki; Hiroyoshi Yamada; Akira NagashimaMitsuhiro KondoYoshiaki ShimadaKeitaro KadonoKosei Yoshihara

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Synthesis and structure activity relationships of carbamimidoylcarbamate derivatives as novel vascular adhesion protein-1 inhibitors

机译：Synthesis and structure activity relationships of carbamimidoylcarbamate derivatives as novel vascular adhesion protein-1 inhibitors

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Graphical abstract Display Omitted Abstract Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted structural optimization of the glycine amide derivative 1 , which we previously reported as a novel VAP-1 inhibitor, to improve stability in dog and monkey plasma, and aqueous solubility. By chemical modification of the right part in the glycine amide derivative, we identified the carbamimidoylcarbamate derivative 20c , which showed stability in dog and monkey plasma while maintaining VAP-1 inhibitory activity. We also found that conversion of the pyrimidine ring in 20c into saturated rings was effective for improving aqueous solubility. This led to the identification of 28a and 35 as moderate VAP-1 inhibitors with excellent aqueous solubility. Further optimization led to the identification of 2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate ( 40b ), which showed similar human VAP-1 inhibitory activity to 1 with improved aqueous solubility. 40b showed more potent ex vivo efficacy than 1 , with rat plasma VAP-1 inhibitory activity of 92% at 1h after oral administration at 0.3mg/kg. In our pharmacokinetic study, 40b showed good oral bioavailability in rats, dogs, and monkeys, which may be due to its improved stability in dog and monkey plasma.

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来源
《Bioorganic and medicinal chemistry》 |2017年第21期|6024-6038|共15页
作者
Susumu Yamaki; Hiroyoshi Yamada; Akira NagashimaMitsuhiro KondoYoshiaki ShimadaKeitaro KadonoKosei Yoshihara;
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Drug Discovery Research, Astellas Pharma Inc.;

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正文语种英语
中图分类药学;
关键词
Vascular adhesion protein-1; Diabetic nephropathy; Carbamimidoylcarbamate; Stability in plasma; Aqueous solubility;

Synthesis and structure activity relationships of carbamimidoylcarbamate derivatives as novel vascular adhesion protein-1 inhibitors

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