Enhancing Thrombostatin's Oral Delivery

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药物，用于治疗急性冠状动脉综合征（ACS）患者以及受凝血酶促有丝分裂作用影响的癌症患者。目前急性冠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/抗血小板活性的药物（如肝素）均通过静脉给药。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毒理学研究，以申请IND用于人体静脉注射。该化合物基于一系列新的五肽化合物，由D和合成氨基酸组成，这些氨基酸来自缓激肽的ACE分解产物。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（PAR 1和4）的凝血酶激活拮抗剂的潜力。在目前的提案中，我们的目标是通过对肽结构进行化学修饰以使化合物更具亲脂性来提高最新一代血栓抑制素的口服生物利用度。这个阶段1 SBIR提案的具体目标是：具体目标#1：合成掩蔽的凝血酶抑制素类似物：我们将合成一系列我们的领先凝血酶抑制素类似物，以减少电荷并增加肽的疏水性。具体目标#2：血栓抑制素类似物的肠吸收的评价：将评价新的血栓抑制素类似物的肠稳定性和增强的口服转运。具体目标#3：血栓抑制素类似物的口服抗血栓形成活性的测试：新型口服血栓抑制素类似物的体外和体内抗凝血酶活性的测试。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，以创建用于急性冠状动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新的口服药物来治疗心脏病发作和癌症。

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.