发现了一系列新型的中型循环肠酶抑制剂
Fumiaki Kikuchi1, Zenichi Ikeda1, Keiko Kakegawa1
1Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Bioorganic & medicinal chemistry
|September 8, 2023
概括
开发了新的乳抑制剂来抑制肠酶 (一种对蛋白质消化至关重要的酶). 这些化合物在体内表现出强大的疗效和低系统性暴露,为消化系统疾病提供了有前途的治疗方法.
科学领域:
- 生物化学 生物化学
- 药理学 药理学是指药理学的学科.
- 药物发现 药物发现 药物发现
背景情况:
- 肠酶是十二指肠中的一个关键酶,对于肠道蛋白质消化至关重要.
- 之前的研究发现了有限的全身暴露的肠酶抑制剂.
研究的目的:
- 发现具有增强体内疗效的新型肠酶抑制剂.
- 为了保持新开发的抑制剂的低系统暴露.
主要方法:
- 基于机制的药物设计,包括将2转化为中型乳.
- 优化环之间的链接器,以产生乳6b.
- 在小鼠体内有效性评估,包括便蛋白输出分析和全身暴露评估.
主要成果:
- 循环乳显示出强大的肠酶抑制活性,并改善了稳定性.
- 乳6b以太表现出优越的肠酶抑制和长时间的作用.
- 在小鼠中,口服6b显著增加了便蛋白产量,系统吸收低.
- 为6b确定了一种可扩展的10个成员的乳化合成方法.
结论:
- 基于乳的新型肠酶抑制剂在体内具有强大的疗效和低系统性暴露.
- 乳6b以太代表了针对蛋白质消化治疗应用的有希望的候选人.
- 开发的可扩展合成方法促进了潜在的临床开发.
更多相关视频
10:33Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
Published on: October 26, 2015
11.4K
10:12Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
Published on: September 19, 2022
2.1K
相关概念视频
Dipeptidyl Peptidase 4 Inhibitors
211
Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a...
211
Glucagon-like Receptor Agonists
357
Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
357
Enzyme Inhibition
78.6K
Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
78.6K
Acid Suppressive Drugs for Peptic Ulcer Disease: Proton Pump Inhibitors
463
Peptic ulcers, often induced by H. pylori infections or NSAID usage, arise from disruptions in the delicate balance of gastric acid production. Peptic ulcers stem from heightened gastric acid levels due to H. pylori infections or NSAID use. The protective mucus layer diminishes in the presence of these factors, allowing gastric acid to erode the stomach lining and form ulcers.
Gastric acid, a potent cocktail of hydrogen and chloride ions, is produced in specialized parietal cells within the...
Gastric acid, a potent cocktail of hydrogen and chloride ions, is produced in specialized parietal cells within the...
463
