Non-Sedating Atropisomeric Drugs for Atopic Disease

项目描述（由申请人提供）：本项目的目标是开发治疗特应性皮炎、哮喘和过敏性鼻炎的口服药物。SAR研究已经产生了两种先导化合物，与以前使用的同类药物相比，它们显示出更高的效力和显著减少的副作用。值得注意的是，由于收缩异构，这两个先导化合物是手性的。虽然在物理有机化学中有很好的先例，但反旋异构是药物或候选药物表现出的一种相当罕见的手性形式，并为开发这些化合物增加了一层复杂性。本项目的具体目标是：1。研究合成先导化合物的对映体（对映体）的高效方法，以获得高收率和高对映体含量。2. 目的：确定先导化合物的缩合异构体的物理化学性质，从而确定其手性稳定性，从而确定最佳的盐形式，以确保高ee的保质期。3. 研究和对比先导化合物的体外代谢和体内代谢的药代动力学，以帮助选择每种化合物的最佳阿托品进行临床前开发。

DESCRIPTION (provided by applicant): The present project's goal is to develop oral medications for the treatments of atopic dermatitis, asthma and allergic rhinitis. SAR studies have produced two lead compounds that show increased potency and markedly reduced side affects compared with previously used drugs of this class. Notably, the two lead compounds are chiral due to atropisomerism. Though well precedented in physical organic chemistry, atropisomerism is a rather uncommon form of chirality exhibited by drugs or drug candidates, and adds a layer of complexity in developing these compounds. The present project's specific aims are: 1. To develop efficient methods to synthesize atropisomers (enantiomers) of the lead compounds in high chemical yields and in high enantiomeric excess. 2. To determine the physico-chemical properties of the atropisomers of the lead compounds so that the chiral stability can be ascertained, and so that optimal salt forms can be identified that ensure high ee in shelf life. 3. To study and contrast the metabolism of the atropisomers of the lead compounds in vitro and the pharmacokinetics and metabolism in vivo, to aid in selecting the optimal atropisomer of each compound for preclinical development.