Optimizing Drug-like Properties

一种化合物的体内效用，或“药效性”，需要分子到达靶组织在 足够的浓度以产生所需的生物效应。这包括需要一条简单的路线 行政管理。药物代谢和药代动力学(DMPK)项目旨在快速确定关键 复合负债并与其他项目负责人进行沟通，以促进快速优化 铅分子的分子。过去的行业战略强调及早优化目标效力和 没有代谢数据的选择性导致1991年进入临床的40%的分子未能通过PK或 生物利用度原因。由于DMPK的早期加入，PK故障已减少到原来的1/4。在……里面 除了代谢和消除，药效学因素，如血浆蛋白结合， 溶解度、渗透性会影响最终的药效。其他研究以确定潜在的 对于药物-药物相互作用或活性中间体的形成将有助于促进最安全的分子有序 为了提供这类关键信息，将在整个化合物中进行DMPK研究 优化阶段。关于增食欲素受体代谢稳定性和处置的信息 体外和体内的拮抗剂都会迅速传回给药剂师，便于合成 优化。在项目的早期阶段，在这段时间内，正在确定命中目标并确定优先顺序， 对生物利用度和新陈代谢的总体特征进行测量，以消除候选 化合物。随着项目的成熟，将对复合参数进行更密集的测量 对数量较少的精炼铅结构进行指导，以指导其发展。

The in vivo utility, or "drugability", of a compound requires the molecule to reach the target tissues at sufficient concentrations to elicit the desired biological effect. This includes the need for a simple route of administration. The Drug Metabolism and Pharmacokinetics (DMPK) project aims to rapidly determine key compound liabilities and communicate these with the other project heads to facilitate the rapid optimization of the lead molecules. Past industry strategies emphasizing early optimization of target potency and selectivity without metabolism data resulted in 40% of molecules entering the clinic in 1991 failing for PK or bioavailability reasons. PK failures have been reduced 4-fold due to the early incorporation of DMPK. in addition to metabolism and elimination, pharmacodynamic factors, such as plasma protein binding, solubility, and permeability will influence the ultimate efficacy. Additional studies to determine the potential for drug-drug interactions or reactive intermediate formation will help promote the safest molecules In order to provide this type of crucial information, DMPK studies will be performed throughout the compound optimization phase. Information about the metabolic stability and disposition of the orexin receptor antagonists in vitro and in vivo will be rapidly communicated back to the chemists to facilitate compound optimization. At the early stages of the project, during which time hits are being identified and prioritized, measurements of gross features of bioavailability and metabolism will be made to eliminate candidate compounds. As the project matures, more intensive measurements of compound parameters will be made on a smaller numbers of refined lead structures to guide their development.