title: On-rate based optimization of structure-kinetic relationship--surfing the kinetic map.
abstract: 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.
authors.affiliation: Proteros biostructures GmbH, Bunsenstrasse 7a, 82152 Martinsried, Germany. Electronic address: schoop@proteros.com.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schoop
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Fabian
authors.initials: F
authors.lastname: Dey
mesh_terms: D055808:Drug Discovery; D007700:Kinetics; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations; D011506:Proteins