Predicting and tuning physicochemical properties in lead optimization: amine basicities.
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.
Morgenthaler
Martin
M
Laboratorium für Organische Chemie, ETH Zürich, HCI, Hönggerberg, 8093 Zürich, Switzerland.
Schweizer
Eliane
E
Hoffmann-Röder
Anja
A
Benini
Fausta
F
Martin
Rainer E
RE
Jaeschke
Georg
G
Wagner
Björn
B
Fischer
Holger
H
Bendels
Stefanie
S
Zimmerli
Daniel
D
Schneider
Josef
J
Diederich
François
F
Kansy
Manfred
M
Müller
Klaus
K
D000588:Amines / Q000737:chemistry*; D000991:Antithrombins / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D016247:Information Storage and Retrieval
D000588:Amines; D000991:Antithrombins