Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of Novel Tetrahydropyran-Based Thiodisaccharide Mimics as Galectin-3 Inhibitors

Xu Li; Hartz Richard A.; Beno Brett R.; Ghosh Kaushik; Shukla Jinal K.; Kumar Amit; Patel Dipal; Kalidindi Narasimharaju; Lemos Nadine; Gautam Shashyendra Singh; Kumar Anoop; Ellsworth Bruce A.; Shah Devang; Sale Harinath; Cheng Dong; Regueiro-Ren Alicia

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Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of Novel Tetrahydropyran-Based Thiodisaccharide Mimics as Galectin-3 Inhibitors

机译：合成，结构 - 活性关系，以及基于新型四氢吡喃的硫代糖模拟剂作为Galectin-3抑制剂的体内评价

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Galectin-3 is a member of a family of beta-galactoside-binding proteins. A substantial body of literature reports that galectin-3 plays important roles in cancer, inflammation, and fibrosis. Small-molecule galectin-3 inhibitors, which are generally lactose or galactose-based derivatives, have the potential to be valuable disease-modifying agents. In our efforts to identify novel galectin-3 disaccharide mimics to improve drug-like properties, we found that one of the monosaccharide subunits can be replaced with a suitably functionalized tetrahydropyran ring. Optimization of the structure-activity relationships around the tetrahydropyran-based scaffold led to the discovery of potent galectin-3 inhibitors. Compounds 36, 40, and 45 were selected for further in vivo evaluation. The synthesis, structure-activity relationships, and in vivo evaluation of novel tetrahydropyran-based galectin-3 inhibitors are described.

机译：半乳糖凝集素-3是β-半乳糖苷结合蛋白家族的成员。大量文献报道半乳糖凝集素-3在癌症、炎症和纤维化中起重要作用。小分子半乳糖凝集素-3抑制剂通常是基于乳糖或半乳糖的衍生物，有可能成为有价值的疾病修饰剂。在我们鉴定新型半乳糖凝集素-3双糖模拟物以改善药物性质的努力中，我们发现其中一个单糖亚基可以被适当功能化的四氢吡喃环取代。围绕四氢吡喃支架的结构-活性关系的优化导致了有效的半乳糖凝集素-3抑制剂的发现。选择化合物36、40和45进行进一步的体内评价。本文介绍了新型四氢吡喃类半乳糖凝集素-3抑制剂的合成、构效关系和体内评价。

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来源
《Journal of Medicinal Chemistry》 |2021年第10期|共22页
作者
Xu Li; Hartz Richard A.; Beno Brett R.; Ghosh Kaushik; Shukla Jinal K.; Kumar Amit; Patel Dipal; Kalidindi Narasimharaju; Lemos Nadine; Gautam Shashyendra Singh; Kumar Anoop; Ellsworth Bruce A.; Shah Devang; Sale Harinath; Cheng Dong; Regueiro-Ren Alicia;
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作者单位

Bristol Myers Squibb Co Res &

Dev Dept Small Mol Drug Discovery Princeton NJ 08543 USA;

Bristol Myers Squibb Co Res &

Dev Dept Small Mol Drug Discovery Princeton NJ 08543 USA;

Bristol Myers Squibb Co Dept Comp Aided Drug Design &

Mol Analyt Res &

Dev Princeton NJ 08543 USA;

Biocon Bristol Myers Squibb Res &

Dev Ctr Bangalore 560099 Karnataka India;

Biocon Bristol Myers Squibb Res &

Dev Ctr Bangalore 560099 Karnataka India;

Biocon Bristol Myers Squibb Res &

Dev Ctr Bangalore 560099 Karnataka India;

Bristol Myers Squibb Co Res &

Dev Dept Metab &

Pharmacokinet Princeton NJ 08543 USA;

Biocon Bristol Myers Squibb Res &

Dev Ctr Bangalore 560099 Karnataka India;

Biocon Bristol Myers Squibb Res &

Dev Ctr Bangalore 560099 Karnataka India;

Biocon Bristol Myers Squibb Res &

Dev Ctr Bangalore 560099 Karnataka India;

Biocon Bristol Myers Squibb Res &

Dev Ctr Bangalore 560099 Karnataka India;

Bristol Myers Squibb Co Res &

Dev Dept Small Mol Drug Discovery Princeton NJ 08543 USA;

Biocon Bristol Myers Squibb Res &

Dev Ctr Bangalore 560099 Karnataka India;

Biocon Bristol Myers Squibb Res &

Dev Ctr Bangalore 560099 Karnataka India;

Bristol Myers Squibb Co Res &

Dev Dept Cardiovasc &

Fibrosis Discovery Biol Princeton NJ 08543 USA;

Bristol Myers Squibb Co Res &

Dev Dept Small Mol Drug Discovery Princeton NJ 08543 USA;

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正文语种 eng
中图分类药学;
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Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of Novel Tetrahydropyran-Based Thiodisaccharide Mimics as Galectin-3 Inhibitors

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