Hahn Christian, Erb Klaus Joseph
Department of Pulmonary Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach a. d. Riss, Germany.
Curr Drug Targets. 2008 Jun;9(6):443-51. doi: 10.2174/138945008784533552.
Identifying and developing novel chemical entities (NCE) for the treatment of asthma is a time-consuming process and liabilities that endanger the successful progression of a compound from research into the patient are found throughout all phases of drug discovery. In particular the failure of advanced compounds in clinical studies due to lack of efficacy and/or safety concerns is tremendously costly. Therefore, in order to try and reduce the failure rate in clinical trials various in vitro and in vivo tests are performed during preclinical development, to rapidly identify liabilities, eliminate high risk compounds and promote promising potential drug candidates. To achieve this objective, numerous prerequisites have to be met regarding the physico-chemical properties of the compound, and bioactivity or model systems are needed to rate the therapeutic potential of new compounds. Drug liabilities such as target and species specificity, formulation issues, pharmacokinetics as well as pharmacodynamics and the toxic potential of the compound have to be analyzed in great detail before a compound can enter a clinical trial. A particularly challenging aspect of developing novel NCEs for the treatment of asthma is choosing and setting up in vivo models believed to be predictive for human disease. Numerous companies have in the past and are currently developing NCEs targeting many different pathways and cells with the aim to treat asthma. However, currently the only NCE having a significant market share are long-acting beta-agonists (LABA), inhaled and orally active steroids and leukotriene receptor antagonists. In the past many novel NCE for the treatment of asthma were effective in animal models but failed in the clinic. In this review we outline the prerequisites of novel NCE needed for clinical development.
识别和开发用于治疗哮喘的新型化学实体（NCE）是一个耗时的过程，在药物发现的各个阶段都可能出现危及化合物从研究成功推进到临床应用的不利因素。特别是，由于缺乏疗效和/或安全性问题，晚期化合物在临床研究中失败的代价极其高昂。因此，为了试图降低临床试验中的失败率，在临床前开发阶段会进行各种体外和体内试验，以快速识别不利因素，淘汰高风险化合物，并推动有潜力的候选药物。为实现这一目标，必须满足关于化合物物理化学性质的众多先决条件，并且需要生物活性或模型系统来评估新化合物的治疗潜力。在化合物进入临床试验之前，必须详细分析诸如靶点和物种特异性、制剂问题、药代动力学以及药效学和化合物的潜在毒性等药物不利因素。开发用于治疗哮喘的新型NCE的一个特别具有挑战性的方面是选择和建立被认为可预测人类疾病的体内模型。过去和现在都有许多公司在开发针对多种不同途径和细胞的NCE，旨在治疗哮喘。然而，目前唯一具有显著市场份额的NCE是长效β-激动剂（LABA）、吸入和口服活性类固醇以及白三烯受体拮抗剂。过去，许多用于治疗哮喘的新型NCE在动物模型中有效，但在临床中失败了。在这篇综述中，我们概述了临床开发所需的新型NCE的先决条件。
