IMPROVING BIOAVAILABILITY OF RGD PEPTIDOMIMETICS

描述：血栓性疾病是死亡的主要原因之一， 美国;此外，150多万人 因心肌梗塞住院的病人 出现 RGD-肽模拟物衍生物的开发取得了巨大进展， 抗血栓剂，这可能会导致药物，以打击 血栓形成 不幸的是，RGD-肽模拟物具有较差的口服给药效果。 生物利用度，因为它们具有不利于 通过细胞膜的渗透，这是肽的常见问题， 和肽模拟物。 RGD-肽模拟物的低膜渗透性是 由于它们的物理化学性质，包括尺寸、电荷， 溶解性、氢键键合势、酶稳定性和构象。 本提案探讨了暂时改变 一些已知的RGD-肽模拟物的物理化学性质增加 它们通过实施环状药物来渗透膜的能力 在我们的实验室中开发的方法。 因此，这一目标 建议由RGD-肽模拟物（1a）合成环状前药（1）， 并研究它们渗透细胞膜的能力， 母体化合物 的环状前药的形成 RGD-肽模拟物（1）将暂时掩盖不利的 理化性质的母体药物，并将减少收费 和氢键的潜力，提高酶的稳定性和诱导 折叠以形成紧凑的结构。 因此，物理上的变化 这些特性可以改善它们通过细胞膜的渗透。 后 环状前药1穿过细胞膜，可被酯酶水解 释放母体化合物1a。 细胞膜的改良 RGD-肽模拟物的环状前药的渗透与它们的 将使用Caco-2细胞培养物评价相应的母体化合物 模型和大鼠肠灌流模型。 理化 环状前药的性质将被用来解释细胞膜 环状前药和母体化合物的渗透特性。 前药和母体化合物的几个理化性质 将进行评估，包括溶解度，氢键潜力，平均 流体动力学体积、分配系数、亲脂性和 构象 本发明的环状前药的酶促稳定性 HIV蛋白酶抑制剂将在不同的生物培养基中进行检测 包括大鼠肠匀浆、大鼠肝匀浆、Caco-2细胞 匀浆、人血浆和分离的酶。 的生物活性 RGD-肽模拟物环状前药及其各自的母体 将对化合物进行评价。

DESCRIPTION: Thrombotic disease is one of the major causes of death in the U.S.; in addition, more than one and one-half million people are hospitalized with myocardial infarctions each year. There has been tremendous progress in the development of RGD-peptidomimetic-derived antithrombotic agents, which may potentially lead to drugs to combat thrombosis. Unfortunately, RGD-peptidomimetics have poor oral bioavailability because they have physicochemical properties unfavorable to permeation through cell membranes, which is a common problem for peptides and peptidomimetics. The low membrane permeation of RGD-peptidomimetics is due to their physicochemical properties , including size, charge, solubility, hydrogen-bonding potential, enzyme stability and conformation. This proposal investigates the possibility of temporarily changing the physicochemical properties of some known RGD-peptidomimetics to increase their ability to permeate membranes by implementing the cyclic drug methodology, developed in our laboratory. Therefore, the objectives of this proposal are to synthesize cyclic prodrugs (1) from RGD-peptidomimetics (1a) and to study their ability to permeate cell membranes compared to that of the parent compound. The formation of cyclic prodrugs of RGD-peptidomimetics (1) will transiently mask the unfavorable physicochemical properties of the parent drug and will reduce the charges and hydrogen-bonding potential, improve enzymatic stability and induce folding to form a compact structure. Therefore, the change in physical properties can improve their permeation through cell membranes. After crossing the cell membrane, cyclic prodrug 1 can be hydrolyzed by esterase to release the parent compound 1a. The improvement of cell membrane permeation of the cyclic prodrug of RGD-peptidomimetics compared to their respective parent compounds will be evaluated using the Caco-2 cell culture model and the intestinal rat perfusion model. The physicochemical properties of the cyclic prodrugs will be used to explain the cell membrane permeation characteristics of the cyclic prodrugs an the parent compounds. Several physicochemical properties of the prodrugs and the parent compounds will be evaluated, including solubility, hydrogen bonding potential, average hydrodynamic volumes, partition coefficients, lipophilicity and conformation. The enzymatic stability of the cyclic prodrugs of HIV-protease inhibitors will be examined in different biological media including rat intestinal homogenates, rat liver homogenates, Caco-2 cell homogenates, human plasma and isolated enzymes. The biological activity of the cyclic prodrugs of RGD-peptidomimetics and their respective parent compounds will be evaluated.