title: Amine promiscuity and toxicology analysis.
abstract: Drug discovery programs often face challenges to obtain sufficient duration of action of the drug (i.e. seek longer half-lives). If the pharmacodynamic response is driven by free plasma concentration of the drug then extending the plasma drug concentration is a valid approach. Half-life is dependent on the volume of distribution, which in turn can be dependent upon the ionization state of the molecule. Basic compounds tend to have a higher volume of distribution leading to longer half-lives. However, it has been shown that bases may also have higher promiscuity. In this work, we describe an analysis of in vitro pharmacological profiling and toxicology data investigating the role of primary, secondary, and tertiary amines in imparting promiscuity and thus off-target toxicity. Primary amines are found to be less promiscuous in in vitro assays and have improved profiles in in vivo toxicology studies compared to secondary and tertiary amines.
authors.affiliation: Medicine Design, Pfizer Worldwide Research & Development, Cambridge, MA 02139, United States. Electronic address: esther.lee2@pfizer.com.
authors.forename: Esther C Y
authors.initials: EC
authors.lastname: Lee
authors.affiliation: Research Statistics, Pfizer Worldwide Research & Development, Groton, CT 06340, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Steeno
authors.affiliation: Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Anne Mai
authors.initials: AM
authors.lastname: Wassermann
authors.affiliation: Computational Sciences, Pfizer Worldwide Research & Development, Cambridge, MA 02139, United States.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Computational Sciences, Pfizer Worldwide Research & Development, Cambridge, MA 02139, United States.
authors.forename: Falgun
authors.initials: F
authors.lastname: Shah
authors.affiliation: Medicine Design, Pfizer Worldwide Research & Development, Cambridge, MA 02139, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D000072237:ERG1 Potassium Channel / Q000737:chemistry / Q000378:metabolism; D006207:Half-Life; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human
keywords: Amines; Half-life; Pharmacological profiling; Promiscuity; Toxicology