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用药物，用于治疗急性冠脉综合征(ACS)患者以及其癌症受到凝血酶促分裂作用影响的患者。目前治疗急性冠脉综合征的方法是联合应用抗凝/抗血小板药物和经皮冠状动脉腔内成形术。许多常规用于抗凝/抗血小板活性的药物，如肝素，都是静脉给药。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，凝血酶是一种促凝血蛋白，近年来也被认为是一种强有力的有丝分裂原，其抑制作用可能会影响肿瘤的生长和转移。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，用于静脉注射用于人类的IND。该化合物基于一系列新的五肽化合物，由D和从缓激肽的ACE分解产物中衍生的合成氨基酸组成。这些化合物统称为“血栓抑制素”，显示出作为凝血酶抑制剂和凝血酶激活的血小板蛋白酶激活受体1和4(PAR1和4)的拮抗剂的潜力。在目前的提案中，我们的目标是通过对多肽结构进行化学修饰来提高最新一代凝血酶的口服生物利用度，以使化合物更具亲脂性。此第一阶段SBIR建议的具体目标是：特定目标#1：合成掩蔽的血栓抑素类似物：我们将合成一系列我们的先导血栓抑素类似物，以减少电荷并增加多肽的疏水性。具体目标#2：评估血栓抑素类似物的肠道吸收：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。具体目标#3：测试口服血栓抑素类似物的抗血栓形成活性：测试新的口服血栓抑素类似物在体外和体内的抗凝血酶活性。这项拟议的工作旨在提高凝血酶抑素类似物的胃肠道生物利用度，以创造一种口服凝血酶和凝血酶受体激活拮抗剂，用于急性冠脉综合征和癌症治疗。该项目特别涉及开发一种治疗心脏病发作和癌症的新型口服药物。

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.