Schoop Andreas, Dey Fabian
Proteros biostructures GmbH, Bunsenstrasse 7a, 82152 Martinsried, Germany.
Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Drug Discov Today Technol. 2015 Oct;17:9-15. doi: 10.1016/j.ddtec.2015.08.003. Epub 2015 Sep 18.
In the lead discovery process residence time has become an important parameter for the identification and characterization of the most efficacious compounds in vivo. To enable the success of compound optimization by medicinal chemistry toward a desired residence time the understanding of structure-kinetic relationship (SKR) is essential. This article reviews various approaches to monitor SKR and suggests using the on-rate as the key monitoring parameter. The literature is reviewed and examples of compound series with low variability as well as with significant changes in on-rates are highlighted. Furthermore, findings of kinetic on-rate changes are presented and potential underlying rationales are discussed.
在先导化合物发现过程中，驻留时间已成为体内鉴定和表征最有效化合物的一个重要参数。为了使药物化学能够成功地优化化合物以达到所需的驻留时间，理解结构-动力学关系（SKR）至关重要。本文综述了监测SKR的各种方法，并建议将结合速率作为关键监测参数。对相关文献进行了综述，并重点介绍了结合速率变化小以及结合速率有显著变化的化合物系列实例。此外，还介绍了动力学结合速率变化的研究结果，并讨论了潜在的基本原理。
