Non-Sedating Atropisomeric Drugs for Atopic Diseases

描述（由申请人提供）：在我们开发非镇静酮替芬类似物的项目中，我们发现去甲酮替芬（NORK）和n-羟乙基-去甲酮替芬（HENK）具有显著的平喘和抗炎活性，但镇静和抗毒菌活性不如酮替芬。由于收缩异构，这些化合物具有手性。因此，我们制备了单个atropisomer，并表明S-NORK和S-HENK比外消旋体具有更大的治疗活性，并且r -atropisomer具有更大的镇静和抗ususcaric副作用。在第一阶段，我们评估了候选化合物的制备方法、化学和代谢稳定性，以确定是否有必要进一步开发这类异构体。此外，我们还比较了它们的生物稳定性，并开始研究它们的药代动力学性质。我们得出结论，NORK和HENK的反旋异构体在固体状态下是稳定的，在水溶液中不太稳定，但在温度依赖的方式下，在生物环境中手性稳定。在二期试验中，我们选择诺酮替芬的s -异构体（“SNORK”）作为“最终先导化合物”，s -羟乙基-诺酮替芬（“SHENK”）作为备用化合物。该二期项目的具体目标是：1。改进合成方法，使SNORK的化学收率高，对映体含量高。2. 制定和验证适用于中间体和原料药分析的分析方法。3. 利用人微粒体和肝细胞进行SNORK体外代谢研究，并在相关动物体内进行代谢研究。4. 制备约1公斤gmp级SNORK用于首次人体研究。5. 使用本申请中描述的方法进行额外的药理学研究和安全药理学研究。6. 进行监管部门批准IND所需的毒理学研究。撰写SNORK的IND申请，与FDA进行IND前会议，并向FDA提交IND申请。目的是将该项目授权给具有药物开发和监管批准经验的公司，并有能力在美国和全球范围内将该药物商业化。这项工作的成功结束将提供第一个由FDA批准用于临床试验的atrosomomer药物的例子。

DESCRIPTION (provided by applicant): In our program to develop non-sedating ketotifen analogs, we found that norketotifen (NORK) and N-hydroxyethyl-norketotifen (HENK) had significant antiasthmatic and anti-inflammatory activity but less sedation and antimuscarinic activity than ketotifen. These compounds are chiral as a result of atropisomerism. We, therefore, prepared the individual atropisomers, and showed that S-NORK and S-HENK had greater therapeutic activity than the racemates, and that the R-atropisomers had greater sedative and antimuscarinic side effects. In phase I we evaluated the preparation methods, and chemical and metabolic stability of atropisomers of the candidate compounds in order to decide if further development of this class of isomers was warranted. In addition, we have compared the biological stability and began to study pharmacokinetic properties of the atropisomers for the same purpose. We conclude that the atropisomers of NORK and HENK are stable in the solid state, less stable in aqueous solution, but in a temperature-dependent manner, and chirally stable in biological milieus. For phase II we have chosen as "ultimate lead compound" the S-isomer of norketotifen ("SNORK"), and S-hydroxyethyl-norketotifen (SHENK) as a backup compound. The specific aims for this phase II project are: 1. To improve synthetic methods to manufacture SNORK in high chemical yield and in high enantiomeric excess. 2. To develop and validate analytical methods suitable for analysis of intermediates and drug substance. 3. To perform metabolism studies of SNORK in vitro, using human microsomes and hepatocytes, and in vivo, in relevant animals. 4. To prepare ca. one kilogram of GMP-grade SNORK for first in man studies. 5. To perform additional pharmacological studies and safety pharmacological studies, using methodology described in this application. 6. To perform toxicological studies necessary for regulatory approval of an IND. 7. To write an IND application for SNORK, to conduct a pre-IND meeting with the FDA, and to file the IND with the FDA. The aim is to license this project to a company with experience in drug development and regulatory approval, and the ability to commercialize the drug in the U.S. and worldwide. Successful conclusion of this work will afford the first example of an atropisomeric drug approved for clinical trials by the FDA.