Design and Synthesis of HIV-1 Protease Inhibitors

描述：（申请人的描述）04-07年的主要目标 AI-42010的作用是：（A）为了增强我们的3，5-连接的（氮）-N-甲基-N-甲基- 取代的）吡咯啉酮FIIV-1蛋白酶抑制剂，通过（1）优化 Asp 29（N-H）/抑制剂（氨基甲酸酯C=O）氢键作用;（2）提高了 （B）为了设计和合成一种在S2结合口袋处的结合相互作用， 第二代HIV-1蛋白酶抑制剂，基于2，5-连接的（羰基 取代的）吡咯啉酮骨架，其在P2处并入氨基甲酸酯部分; (C)为了提高我们的MMP抑制剂的效力， （D）设计和合成一系列的P1'侧链， 谷胱甘肽S-转移酶的3，5-连接吡咯啉酮抑制剂。的 我们新开发的固体支撑吡咯啉酮化学的可用性将 大大加强了这些努力（见下文）。 为了支持对各种3，5-连接的吡咯啉酮的需求，我们还将（E） 将我们的三步迭代固体支撑合成方法扩展到更有效的 2-使用不饱和α-氨基内酯的分步方案。这个合成企业 （F）发展一个有效的综合所需的 具有编码或非编码的不饱和α-氨基内酯结构单元 氨基酸侧链。然后，我们将（G）详细说明针对以下目标的重点库： 发现了改良的MMP酶抑制剂。在2，5-链接 在聚吡咯啉酮领域，我们将开发（H）收敛合成方案。 确定（氮置换）的溶液构象特征 聚吡咯啉酮支架，我们将（I）进行聚集和 一系列3，5-连接聚吡咯啉酮的光谱研究。最后我们 将（J）完成3，5-连接的四吡咯啉酮β-转角的合成 模拟物，（K）测试其对生长抑素受体的生物活性，和（L） 将3，5-连接的三吡咯啉酮掺入到十二肽序列上， 探索使用氮置换的吡咯啉酮基序来模拟螺旋 肽的结构。

DESCRIPTION: (Applicant's Description) The principal aims for the 04-07 years of AI-42010 are: (A) To enhance the potency of our 3,5-linked (nitrogen displaced) pyrrolinone FIIV-1 protease inhibitors via (1) optimization of the Asp29 (N-H)/inhibitor (carbamate C=O) hydrogen-bond and (2) improvement of the binding interaction at the S2 binding pocket; (B) To design and synthesize a second-generation HIV-1 protease inhibitor based on the 2,5-linked (carbonyl displaced) pyrrolinone scaffold which incorporates a carbamate moiety at P2; (C) To improve the potency of our MMP inhibitors by increasing the size and length of the P1' side-chains; and (D) To design and synthesize a series of 3,5-linked pyrrolinone inhibitors for the enzyme glutathione S-transferase. The availability of our newly developed solid-support pyrrolinone chemistry will significantly augment these efforts (vide infra). To support the demand for varied 3,5-linked pyrrolinones, we will also (E) extend our 3-step iterative solid-support synthetic method to a more efficient 2-step protocol employing unsaturated a-aminolactones. This synthetic venture will require (F) the development an effective synthesis of the requisite unsaturated a-aminolactone building blocks possessing both coded or non-coded amino acid side chains. We will then (G) elaborate focused libraries aimed at the discovery of improved MMP enzyme inhibitors. In the 2,5-linked polypyrrolinone area, we will develop (H) a convergent synthetic protocol. To define the solution conformational features of the (nitrogen displaced) polypyrrolinone scaffold, we will (I) perform both aggregation and spectroscopic studies on a series of 3,5-linked polypyrrolinones. Finally, we will (J) complete the synthesis of a 3,5-linked tetrapyrrolinone beta-turn mimetic, (K) test its biological activity at the somatostatin receptor, and (L) incorporate a 3,5-linked trispyrrolinone onto a dodecapeptide sequence to explore the use of the nitrogen displaced pyrrolinone motif to mimic helical structures in peptides.