Enhancing Thrombostatin's Oral Delivery

增强凝血酶抑制素的口服递送

• 批准号: 7152961
• 负责人: John M Hilfinger
• 金额: $ 27.45万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7152961
• 关键词: acute disease /disorder; analog; antineoplastics; antithrombins; coronary disorder; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; gastrointestinal absorption /transport; heart disorder chemotherapy; inhibitor /antagonist; laboratory mouse; laboratory rat; neoplasm /cancer chemotherapy; oral administration; peptide structure; pharmacokinetics; thrombin; thrombin receptor

DESCRIPTION (provided by applicant): The long term objective of the project is to develop an orally bioavailable drug for treatment of individuals with acute coronary syndromes (ACS) and also individuals whose cancer is influenced by the mitogenic effects of thrombin. Current therapy for the acute coronary syndrome is a combination of anticoagulant/antiplatelet agents and percutaneous transluminal coronary angioplasty. Many of the agents routinely used for anticoagulant/antiplatelet activity, such as heparin, are administered intravenously. Other oral agents attack specific platelet targets like the ADP receptor (clopidogrel) or platelet cyclooxygenase (aspirin). Moreover, in recent years, thrombin, a procoagulant protein, has also been recognized as a potent mitogen and its inhibition may influence cancer growth and metastasis. We are aiming to develop an orally available thrombin inhibitor and thrombin receptor activation antagonist. Presently, we have a lead compound undergoing toxicology studies for an IND application for intravenous use in man. This compound is based upon a novel series of pentapeptide compounds consisting of D and synthetic amino acids derived from the ACE breakdown product of bradykinin. These compounds, collectively termed "Thrombostatins," show potential as inhibitors of thrombin and antagonists of thrombin activation of platelet protease activated receptors 1 and 4 (PAR1 and 4). In the current proposal, we aim to improve the oral bioavailability of the latest generation of Thrombostatins by chemical modification of the peptide structure in order to make the compound more lipophilic. The specific aims of this Phase 1 SBIR proposal are: Specific Aim #1: Synthesis of Masked Thrombostatin Analogs: We will synthesize a series of analogs of our lead Thrombostatin analog in order to reduce the charge and increase the hydrophobicity on the peptide. Specific Aim #2: Evaluation of Intestinal Absorption of the Thrombostatin Analogs: The new Thrombostatin analogs will be evaluated for intestinal stability and enhanced oral transport. Specific Aim #3: Testing of the Thrombostatin Analogs for oral anti-thrombosis activity: Testing of the novel oral Thrombostatin analogs for anti-thrombin activity in vitro and in vivo. The proposed work aims to advance the gastrointestinal bioavailability of Thrombostatin analogs to create an orally available thrombin and thrombin receptor activation antagonist for acute coronary syndrome and cancer therapy. This project specifically involves the development of a new oral drug to treat heart attacks and cancer.

描述（由申请人提供）：该项目的长期目标是开发一种口服生物可利用的药物，用于治疗患有急性冠状动脉综合征（ACS）的个体以及癌症受凝血酶促有丝分裂作用影响的个体。目前对急性冠状动脉综合征的治疗是抗凝/抗血小板药物和经皮冠状动脉腔内成形术的组合。许多常规用于抗凝血/抗血小板活性的药物，例如肝素，都是静脉内施用的。其他口服药物攻击特定的血小板靶点，如 ADP 受体（氯吡格雷）或血小板环氧合酶（阿司匹林）。此外，近年来，凝血酶（一种促凝血蛋白）也被认为是一种有效的有丝分裂原，其抑制可能会影响癌症的生长和转移。我们的目标是开发一种口服凝血酶抑制剂和凝血酶受体激活拮抗剂。目前，我们有一种先导化合物正在进行人体静脉注射 IND 应用的毒理学研究。该化合物基于一系列新型五肽化合物，由衍生自缓激肽 ACE 分解产物的 D 和合成氨基酸组成。这些化合物统称为“凝血酶抑制素”，显示出作为凝血酶抑制剂和血小板蛋白酶激活受体1和4（PAR1和4）的凝血酶激活拮抗剂的潜力。在当前的提案中，我们的目标是通过对肽结构进行化学修饰，使化合物更具亲脂性，从而提高最新一代凝血酶抑制素的口服生物利用度。该第一阶段 SBIR 提案的具体目标是： 具体目标#1：掩蔽凝血酶抑制素类似物的合成：我们将合成我们的主要凝血酶抑制素类似物的一系列类似物，以减少电荷并增加肽的疏水性。具体目标#2：凝血酶抑制素类似物的肠道吸收评估：将评估新的凝血酶抑制素类似物的肠道稳定性和增强的口服转运。具体目标#3：测试凝血酶抑制素类似物的口服抗血栓形成活性：测试新型口服凝血酶抑制素类似物的体外和体内抗凝血酶活性。拟议的工作旨在提高凝血酶抑制素类似物的胃肠道生物利用度，以创建用于急性冠脉综合征和癌症治疗的口服凝血酶和凝血酶受体激活拮抗剂。该项目具体涉及开发一种治疗心脏病和癌症的新型口服药物。