Optimizing Drug-like Properties

化合物的体内效用或“可药用性”要求分子以约100 μ g/ml的浓度到达靶组织。 足够的浓度以引起所需的生物效应。这包括需要一个简单的路线， 局药物代谢和药代动力学（DMPK）项目旨在快速确定关键的 复合负债，并与其他项目负责人沟通，以促进快速优化 的铅分子。过去的行业战略强调目标效力的早期优化， 没有代谢数据的选择性导致1991年进入临床的40%的分子不能用于PK或 生物利用度的原因。由于DMPK的早期掺入，PK失败减少了4倍。在 除了代谢和消除外，药效学因素，如血浆蛋白结合， 溶解度和渗透性将影响最终的功效。进一步研究以确定 药物相互作用或反应中间体的形成将有助于促进最安全的分子， 为了提供这类重要信息，将在整个化合物中进行DMPK研究 优化阶段。关于食欲素受体的代谢稳定性和处置的信息 体外和体内的拮抗剂将被迅速地反馈给化学家，以促进化合物的合成。 优化.在项目的早期阶段，在此期间，正在确定和优先考虑命中， 将测量生物利用度和代谢的大体特征，以排除候选 化合物.随着项目的成熟，将对复合参数进行更密集的测量 少量的精细铅结构，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.