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