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Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities
Author(s) -
Morgenthaler Martin,
Schweizer Eliane,
HoffmannRöder Anja,
Benini Fausta,
Martin Rainer E.,
Jaeschke Georg,
Wagner Björn,
Fischer Holger,
Bendels Stefanie,
Zimmerli Daniel,
Schneider Josef,
Diederich François,
Kansy Manfred,
Müller Klaus
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700059
Subject(s) - amine gas treating , chemistry , adme , drug discovery , combinatorial chemistry , cyclic amines , tertiary amine , computational chemistry , organic chemistry , biochemical engineering , biochemistry , in vitro , engineering
This review describes simple and useful concepts for predicting and tuning the p K 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 p K 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 p K 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 p K a prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for p K 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.