Di Li, Kerns Edward H, Carter Guy T
Chemical Technologies, Chemical Sciences, Wyeth Research, Princeton, NJ 08852, USA.
Curr Pharm Des. 2009;15(19):2184-94. doi: 10.2174/138161209788682479.
The pharmaceutical industry is facing an ever increasing challenge to deliver safer and more effective medicines. Traditionally, drug discovery programs were driven solely by potency, regardless of the properties. As a result, the development of non-drug-like molecules was costly, had high risk and low success rate. To meet the challenges, the bar has been rising higher for drug candidates. They not only need to be active, but also drug-like to be advanced to clinical development. Drug-like properties, such as solubility, permeability, metabolic stability and transporter effects are of critical importance for the success of drug candidates. They affect oral bioavailability, metabolism, clearance, toxicity, as well as in vitro pharmacology. Insoluble and impermeable compounds can result in erroneous biological data and unreliable SAR in enzyme and cell-based assays. Rapid metabolism by enzymes and high efflux by transporters can lead to high clearance, short half-life, low systemic exposure and inadequate efficacy. Early property information helps teams make informed decisions and avoids wasting precious resources. Structure-property relationships are essential to guide structural modification to improve properties. High throughput ADME/TOX assays have been implemented and are being widely used to drive drug discovery projects in parallel with activity screening. Property design has become an integrated and inseparable part of the modern drug discovery paradigm. The approach has been proven to be a winning strategy.
制药行业在提供更安全、更有效的药物方面面临着日益严峻的挑战。传统上，药物研发项目仅由效力驱动，而不考虑其他性质。因此，开发非类药物分子成本高昂、风险高且成功率低。为了应对这些挑战，对候选药物的要求越来越高。它们不仅需要具有活性，还需要具备类药物性质才能进入临床开发阶段。类药物性质，如溶解度、渗透性、代谢稳定性和转运体效应，对于候选药物的成功至关重要。它们会影响口服生物利用度、代谢、清除率、毒性以及体外药理学。不溶性和不可渗透性化合物可能会在基于酶和细胞的测定中导致错误的生物学数据和不可靠的构效关系。酶的快速代谢和转运体的高外排作用可能导致高清除率、短半衰期、低全身暴露和疗效不足。早期的性质信息有助于团队做出明智的决策，并避免浪费宝贵的资源。构效关系对于指导结构修饰以改善性质至关重要。高通量药物代谢及药代动力学/药物毒性（ADME/TOX）测定已经实施，并与活性筛选并行广泛用于推动药物研发项目。性质设计已成为现代药物研发模式中一个不可或缺的组成部分。这种方法已被证明是一种成功的策略。
