TRANSPORT CHARACTERISTICS OF PEPTIDE MIMETICS

描述（来自申请人摘要的逐字记录）：在过去的20年里， 药物化学家已经合成了许多肽模拟物（例如，HIV蛋白酶 抑制剂、糖蛋白（gp）IIb/IIIa受体拮抗剂）与新的 治疗适应症（例如，抗病毒（AIDS）、抗血栓形成剂）。这些 肽模拟物含有使它们稳定以水解的结构特征 代谢途径和/或赋予它们独特的结构特征， 优化它们与其大分子靶标的相互作用（例如， 酰胺键的生物电子等排体、转角模拟物）。然而，由于他们的贫穷， 生物制药性质（例如，通过肠道的低渗透性 粘膜和肝脏的高清除率），肽模拟物通常表现出较少的 最佳口服生物利用度。即使当给予肽模拟物时， 一般来说，它们在肠胃外被肝脏迅速清除， 获得对重要目标区域的访问（例如，脑）。因此本研究 该计划的重点是阐明什么影响各种酰胺键生物电子等排体 和构象约束对肽模拟物的渗透 通过肠粘膜和血脑屏障（BBB），并在它们的 肝脏的首过清除。特别感兴趣的是， 涉及转运蛋白，其促进渗透穿过 肠粘膜（例如，寡肽转运蛋白）或限制渗透 穿过肠粘膜和血脑屏障并促进肝脏清除 (e.g.,多药耐药相关蛋白1与多药耐药 相关蛋白（MRP 1，MRP 2））。本研究的主要目的 下一个资助期的计划是：（1）阐明结构-运输 一系列模型肽模拟物的关系， 生物电子等排体和外排转运蛋白（MDR 1， MRP 1，MRP 2）和寡肽转运蛋白;以及（2）确定 这些转运蛋白的底物活性对体内 治疗性肽模拟物的生物药学性质（例如，艾滋病毒 蛋白酶抑制剂、gpIIb/IIIa受体拮抗剂）。知识 这项研究计划将有助于药物化学家 合理设计具有改进的生物制药性质的肽模拟物。

DESCRIPTION (verbatim from applicant's abstract): Over the past 20 years, medicinal chemists have synthesized many peptide mimetics (e.g., HIV protease inhibitors, glycoprotein (gp) IIb/IIIa receptor antagonists) with novel therapeutic indications (e.g., antiviral (AIDS), antithrombotic agents). These peptide mimetics contain structural features that stabilize them to hydrolytic pathways of metabolism and/or endow them with unique structural features that optimize their interactions with their macromolecular target (e.g., bioisosteres of amide bonds, turn mimetics). However, because of their poor biopharmaceutical properties (e.g., low permeation through the intestinal mucosa and high clearance by the liver), peptide mimetics often exhibit less than optimal oral bioavailability. Even when peptide mimetics are administered parenterally, they are in general rapidly cleared by the liver and tend not to gain access to important target areas (e.g., brain). Therefore, this research program is focused on elucidating what effects various amide bond bioisosteres and conformational constraints have on the permeation of peptide mimetics through the intestinal mucosa and the blood-brain barrier (BBB) and on their first pass clearance by the liver. Of particular interest are pathways that involve transporter proteins which either facilitate permeation across the intestinal mucosa (e.g., oligopeptide transporter) or restrict permeation across the intestinal mucosa and the BBB and facilitate clearance by the liver (e.g., multidrug resistance associated protein (MDR1) and multidrug resistance associated proteins (MRP1, MRP2)). The primary objectives of this research program for the next grant period are: (1) to elucidate the structure-transport relationships for a series of model peptide mimetics containing commonly used bioisosteres and conformational constraints with the efflux transporters (MDR1, MRP1, MRP2) and with the oligopeptide transporter; and (2) to determine what impact substrate activity for these transporters have on the in vivo biopharmaceutical properties of therapeutic peptide mimetics (e.g., HIV protease inhibitors, gpIIb/IIIa receptor antagonsits). The knowledge forthcoming from this research program should help medicinal chemists to rationally design peptide mimetics with improved biopharmaceutical properties.