Morgenthaler Martin, Schweizer Eliane, Hoffmann-Röder Anja, Benini Fausta, Martin Rainer E, Jaeschke Georg, Wagner Björn, Fischer Holger, Bendels Stefanie, Zimmerli Daniel, Schneider Josef, Diederich François, Kansy Manfred, Müller Klaus
Laboratorium für Organische Chemie, ETH Zürich, HCI, Hönggerberg, 8093 Zürich, Switzerland.
ChemMedChem. 2007 Aug;2(8):1100-15. doi: 10.1002/cmdc.200700059.
This review describes simple and useful concepts for predicting and tuning the pK(a) values of basic amine centers, a crucial step in the optimization of physical and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pK(a) values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chemistry. Next, the changes in pK(a) of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivatives are systematically analyzed, leading to the derivation of simple rules for pK(a) prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pK(a) predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
本综述描述了预测和调节碱性胺中心pK(a)值的简单实用概念，这是药物发现研究中优化许多先导结构的物理和ADME性质的关键步骤。文章首先以三环凝血酶抑制剂为例进行研究，该抑制剂具有叔胺中心，其pK(a)值可在很宽的范围内调节，从药物化学中常见的约10的通常值到通过（远程）相邻官能团调节至2以下。接下来，系统分析了无环和环状胺在被氟、氧、氮和硫官能团以及羰基和羧基衍生物取代时pK(a)的变化，从而得出pK(a)预测的简单规则。讨论了环状胺中的电子和立体电子效应，并简要概述了新兴的pK(a)预测计算方法。调节胺碱度的规则不仅在药物发现研究中具有重要意义，而且对于新型作物保护剂、有机金属配合物新型胺配体的开发，特别是对于不断发展的胺基有机催化领域也具有重要意义。
