Cyclic Prodrugs of Opioid Peptides

描述(申请人提供)：近年来，在设计和合成具有高亲和力和高选择性的不同类型的阿片肽(Mu、Delta、Kappa)的多肽和多肽仿制药方面取得了巨大的进展。然而，这些合成阿片肽和多肽类药物的生物药学性质较差(例如，对肠粘膜和血脑屏障的低渗透性)，严重限制了其临床开发。在这笔NIDA资助的支持下，我们设计并合成了一种模型阿片肽(DADLE)的酯酶敏感环状前体药物，该药物具有有利于高跨细胞渗透的物理化学性质(疏水性、低氢键潜力、不带电荷)。然而，这些环状前体药物表现出外排转运体(如MDR1、MRP2)的底物活性，限制了它们通过肠粘膜和血脑屏障的渗透。如果血脑屏障中的这些外流转运体被抑制，这些环状前体药物的“固有”渗透系数(PAPP)将比DADLE本身的PAPP值高100-300倍。基于这些令人振奋的观察结果，我们计划在下一个赠款期间集中精力优化环状前体药物的生物药学性能，包括：(I)最大限度地减少其外流转运体的底物活性，从而限制其肠道粘膜和血脑屏障的渗透，同时保持其良好的“固有”渗透特性；(Ii)优化它们在靶组织(脑)中向DADLE的转化，并尽量减少它们在血腔中的转化；(Iii)最大限度地减少它们在肝脏的清除，以增加它们在血液中的滞留时间，从而最大限度地增加前药跨血脑屏障分配的机会。在这一更新申请中提出的研究结果应该允许设计第二代阿片肽环状前体药物，从而在静脉注射后提供最佳的药理效果。或口服给药。

DESCRIPTION (provided by applicant): Tremendous progress has been made in recent years in the design and synthesis of peptides and peptidomimetics with high affinity and high selectivity for the different types (mu, delta, kappa) of opioid peptides. However, the clinical development of these synthetic opioid peptides and peptidomimetics has been seriously limited by their poor biopharmaceutical properties (e.g. low permeation through the intestinal mucosa and the blood-brain barrier). With support from this NIDA grant, we have designed and synthesized esterase-sensitive cyclic prodrugs of a model opioid peptide (DADLE) that exhibit physicochemical properties (hydrophobicity, low hydrogen bonding potential, no charge) favorable for high transcellular permeation. However, these cyclic prodrugs were shown to exhibit substrate activity for efflux transporters (e.g. MDR1, MRP2) which restrict their permeation across the intestinal mucosa and the blood-brain barrier. If these efflux transporters in the blood-brain barrier are inhibited, the "intrinsic" permeability coefficients (Papp) of these cyclic prodrugs are 100-300 fold higher than the Papp value for DADLE itself. Based on these exciting observations, we plan during the next grant period to focus on the optimization of the bio-pharmaceutical properties of the cyclic prodrugs, including: (i) minimizing their substrate activity for the efflux transporters that limit their intestinal mucosal and blood-brain barrier permeation while maintaining their good "intrinsic" permeation characteristics; (ii) optimizing their conversion to DADLE in the target tissue (brain) and minimizing their conversien in the blood compartment; and (iii) minimizing their clearance by the liver so as to increase their residency time in the blood, thus maximizing the opportunity for the prodrug to partition across the blood-brain barrier. The results of the studies proposed in this renewal application should allow for the design of second generation cyclic prodrugs of opioid peptides that will afford optimal pharmacological effects after i.v. or oral administration.