IMPROVING BIOAVAILABILITY OF RGD PEPTIDOMIMETICS

描述：血栓性疾病是老年人死亡的主要原因之一。 美国；此外，超过150万人 每年因心肌梗塞入院治疗。已经有了 RGD类多肽类药物的研究进展 抗血栓药，这可能会导致药物对抗 血栓形成。不幸的是，RGD-肽类药物的口服力很差。 生物利用度，因为它们的物理化学性质不利于 通过细胞膜的渗透，这是多肽的常见问题 和多肽仿制药。RGD-肽类药物的膜渗透性较低 由于它们的物理化学性质，包括大小，电荷， 溶解度、氢键势能、酶稳定性和构象。 这项提案调查了临时更改 一些已知的RGD-肽类药物的物理化学性质增加 它们通过实施环状药物透膜的能力 方法学，由我们实验室开发。因此，这一次的目标是 建议从RGD-肽仿制药(1a)合成环状前体药物(1) 并比较它们对细胞膜的渗透能力。 母体化合物。环状前体药物的形成 RGD-肽仿制药(1)将暂时掩盖不利因素 母体药物的物理化学性质，并将降低电荷 和氢键电位，提高酶的稳定性和诱导 折叠形成紧凑的结构。因此，物理上的变化 这些特性可以改善它们对细胞膜的渗透。之后 穿过细胞膜，环状前体药物1可以被酯酶水解 以释放母体化合物1a。细胞膜的改良 RGD-肽类环状前药的透皮吸收性能比较 将使用Caco-2细胞培养对各自的亲本化合物进行评估 模型和大鼠肠道灌流模型。物理化学 环状前体药物的性质将被用来解释细胞膜 环状前体药物与母体化合物的渗透特性。 前药及其母体化合物的若干物理化学性质 将进行评估，包括溶解度、氢键潜力、平均 水动力体积、分配系数、亲油性和 构象。环状前体药物的酶稳定性研究 HIV-蛋白酶抑制剂将在不同的生物介质中进行检测 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类肽药物的环状前体药物及其各自的母体 将对化合物进行评估。

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.