title: Secondary pharmacology: screening and interpretation of off-target activities - focus on translation.
abstract: Secondary pharmacology is an essential component of drug discovery and is used extensively in the pharmaceutical industry for achieving optimal specificity of new drugs via early hazard identification and off-target mitigation. The importance of this discipline has been achieved by increasing its translational value, based on the recognition of biological target-drug molecule-adverse drug reaction (ADR) associations and integration of secondary pharmacology data with pharmacokinetic parameters. Information obtained from clinical ADRs, from recognition of specific phenotypes of animal models and from hereditary diseases provides increasing regulatory confidence in the target-based approach to ADR prediction and mitigation. Here, we review the progress of secondary pharmacology during the past decade and highlight and demonstrate its applications and impact in drug discovery.
authors.affiliation: Preclinical Safety, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Whitebread
authors.affiliation: Preclinical Safety, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
authors.forename: Berengere
authors.initials: B
authors.lastname: Dumotier
authors.affiliation: Preclinical Safety, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Duncan
authors.initials: D
authors.lastname: Armstrong
authors.affiliation: Preclinical Safety, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fekete
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Shanni
authors.initials: S
authors.lastname: Chen
authors.affiliation: Preclinical Safety, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Global Pharma Development Strategy, Novartis Pharmaceuticals, Basel, Switzerland.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Muller
authors.affiliation: Preclinical Safety, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. Electronic address: Laszlo.urban@novartis.com.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Urban
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D010600:Pharmacology / Q000379:methods; D057170:Translational Research, Biomedical / Q000379:methods*