SYNTHESIS AND TESTING OF A NEW CLASS OF HEPARINOIDS

新型类肝素的合成和测试

• 批准号: 3502068
• 负责人: JOSEPH A TOCE
• 金额: $ 5万
• 依托单位: RELIABLE BIOPHARMACEUTICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3502068
• 关键词: anticoagulants; antithrombins; carbohydrate analog; carbohydrate structure; drug design /synthesis /production; heparin; oral administration; sulfates

DESCRIPTION (Investigator's Abstract): This is a phase I application in which the goal is to develop a therapeutic agent which would replace heparin. Although heparin is the best drug for treatment of thromboembolic disease, it is unstable if administered orally and much therefore be used by the intravenous or subcutaneous route. In addition, the thrombocytopenia and both bleeding and thrombosis, which can emerge as complications of this therapy, remain a clinical problem. Recently, in a preliminary report, a group of sulfonated bislactobionic acid amines have been demonstrated to possess anticoagulant and antiocclusive properties comparable to those currently attainable with commercial heparin. Starting with compounds such as maltose and cellobiose, the disaccharide is oxidized and condensed with short chain diamines and then sulphonated. The applicant's company produces large quantities of lactobionic for stabilization of erythromycin and organs for transplant. During a literature search, the applicant found that sulphonated bis-lactobionic acid amines are potential anticoagulants. In heparin, the 3-0'-sulphate on the middle sugar is essential for anticoagulant activity. The applicants will produce carbohydrates of various structure which may have an improved heparin-like activity. The compounds will be initially tested for anticoagulant properties in phase I and, later in phase II, their antithrombotic activity will be evaluated. The advantage of using maltose as a beginning disaccharide is that it may not be digested to the same degree as other sugars. Cellobiose is another starting disaccharide which may not be cleaved by mammalian digestive enzymes. Also, the compounds are rather small, soluble and may be readily absorbed. These small polymers are also non-toxic. Anticoagulant properties of the final compounds generated will be examined for their ability to prolong the activated partial thromboplastin time and the thrombin time. The standard will be heparin, 175 units/mg. Dr. Tollefsen, one of the consultants, will examine the effects of active compounds on the rate of thrombin inhibition by purified antithrombin III and heparin cofactor II as established in his laboratory.

描述（研究者摘要）：这是一个I期应用程序， 其目标是开发一种治疗剂， 肝素 虽然肝素是治疗血栓栓塞的最佳药物， 疾病，它是不稳定的，如果口服给药，因此可以使用 通过静脉或皮下途径。 此外该 血小板减少症和出血和血栓形成，这可能会出现， 这种治疗的并发症仍然是临床问题。 最近，在一份初步报告中， 酸性胺已被证明具有抗凝剂， 抗闭塞性能与目前使用 市售肝素。 从麦芽糖和 纤维二糖，二糖被氧化并与短链缩合， 二胺，然后磺化。 申请人的公司生产大型 用于稳定红霉素的乳糖酸和用于 移植 在文献检索期间，申请人发现， 磺化的双乳糖酸胺是潜在的抗凝剂。 在 肝素，中间糖上的3- 0 '-硫酸盐对于 抗凝血活性 申请人将产生碳水化合物 可以具有改善的肝素样活性的各种结构。 的 在第一阶段，将首先测试化合物的抗凝血性能 并且，稍后在II期中，将评价它们的抗血栓形成活性。 使用麦芽糖作为起始二糖的优点是， 不能像其他糖一样被消化。 纤维二糖是另一种 不能被哺乳动物消化酶裂解的起始二糖 内切酶 此外，所述化合物相当小，可溶，并且可以容易地被溶解。 全神贯注 这些小聚合物也是无毒的。 抗凝 将检查最终生成的化合物的性质， 延长活化部分凝血活酶时间的能力， 凝血酶时间 标准品为肝素，175单位/mg。 托勒夫森医生 其中一名顾问将研究活性化合物对 纯化抗凝血酶III和肝素对凝血酶的抑制率 在他的实验室中建立的辅助因子II。