title: Systematic Study of the Glutathione (GSH) Reactivity of N-Arylacrylamides: 1. Effects of Aryl Substitution.
abstract: Success in the design of targeted covalent inhibitors depends in part on a knowledge of the factors influencing electrophile reactivity. In an effort to further develop an understanding of structure-reactivity relationships among N-arylacrylamides, we determined glutathione (GSH) reaction rates for a family of N-arylacrylamides independently substituted at ortho-, meta-, and para-positions with 11 different groups common to inhibitor design. We find that substituent effects on reaction rates show a linear Hammett correlation for ortho-, meta-, and para-substitution. In addition, we note a correlation between (1)H and (13)C NMR chemical shifts of the acrylamide with GSH reaction rates, suggesting that NMR chemical shifts may be a convenient surrogate measure of relative acrylamide reactivity. Density functional theory calculations reveal a correlation between computed activation parameters and experimentally determined reaction rates, validating the use of such methodology for the screening of synthetic candidates in a prospective fashion.
authors.affiliation: Departments of Medicinal Chemistry, Pharmacokinetics and Drug Metabolism, Molecular Structure, Discovery Technologies, and Oncology Research, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
authors.affiliation: Departments of Medicinal Chemistry, Pharmacokinetics and Drug Metabolism, Molecular Structure, Discovery Technologies, and Oncology Research, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Laurie P
authors.initials: LP
authors.lastname: Volak
authors.affiliation: Departments of Medicinal Chemistry, Pharmacokinetics and Drug Metabolism, Molecular Structure, Discovery Technologies, and Oncology Research, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Medicinal Chemistry, Pharmacokinetics and Drug Metabolism, Molecular Structure, Discovery Technologies, and Oncology Research, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.affiliation: Departments of Medicinal Chemistry, Pharmacokinetics and Drug Metabolism, Molecular Structure, Discovery Technologies, and Oncology Research, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Tegley
authors.affiliation: Departments of Medicinal Chemistry, Pharmacokinetics and Drug Metabolism, Molecular Structure, Discovery Technologies, and Oncology Research, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Tara
authors.initials: T
authors.lastname: Arvedson
authors.affiliation: Departments of Medicinal Chemistry, Pharmacokinetics and Drug Metabolism, Molecular Structure, Discovery Technologies, and Oncology Research, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: John
authors.initials: J
authors.lastname: McCarter
authors.affiliation: Departments of Medicinal Chemistry, Pharmacokinetics and Drug Metabolism, Molecular Structure, Discovery Technologies, and Oncology Research, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tasker
authors.affiliation: Departments of Medicinal Chemistry, Pharmacokinetics and Drug Metabolism, Molecular Structure, Discovery Technologies, and Oncology Research, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
mesh_terms: D000178:Acrylamides / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D005978:Glutathione / Q000378:metabolism*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D013816:Thermodynamics
chemical_list: D000178:Acrylamides; D005978:Glutathione