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可生物利用药物，用于治疗急性冠状动脉综合征（AC）的个体以及受癌症影响凝血酶有丝分裂作用影响的个体。急性冠状动脉综合征的当前疗法是抗凝/抗血小板药物和经皮易流体冠状动脉血管成形术的组合。许多用于抗凝剂/抗血小板活性（例如肝素）通常用于静脉注射的药物。其他口服剂攻击特定的血小板靶标，例如ADP受体（氯吡格雷）或血小板环氧合酶（阿司匹林）。此外，近年来，凝血蛋白是一种凝血蛋白，也被认为是有效的有丝分裂原，其抑制作用可能会影响癌症的生长和转移。我们的目标是开发口服可用的凝血酶抑制剂和凝血酶受体激活拮抗剂。目前，我们有一种正在进行毒理学研究的铅化合物，用于用于人类静脉内使用的IND应用。该化合物基于一系列新型的五肽化合物，该化合物由Bradykinin的ACE分解产物衍生而成的D和合成氨基酸。这些化合物统称为“血小板蛋白”，表现为凝血酶的抑制剂和血小板蛋白酶活化受体1和4（PAR1和4）的凝血酶激活的抑制剂的潜力。在当前的建议中，我们旨在通过化学修饰肽结构来改善最新一代血栓素的口服生物利用度，以使化合物更具亲脂性。该阶段1 SBIR建议的具体目的是：特定目标＃1：掩盖血栓抑素类似物的合成：我们将合成一系列铅血栓抑素类似物的类似物，以减少电荷并增加肽上的疏水性。特定目标＃2：血栓抑素类似物的肠道吸收评估：将评估新的血栓抑素类似物的肠道稳定性和增强的口服转运。特定目的＃3：血栓抑素类似物的口服抗凝血关系活性：新型口服血栓抑素类似物的测试在体外和体内测试抗脑凝结活性。拟议的工作旨在提高血栓抑素类似物的胃肠道生物利用度，以创建一种口服可用的凝血酶和凝血酶受体激活拮抗剂，用于急性冠状动脉综合征和癌症治疗。该项目特别涉及开发一种新的口服药物来治疗心脏病发作和癌症。