title: MARK inhibitors: Declaring a No-Go decision on a chemical series based on extensive DMPK experimentation.
abstract: Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer's disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro-in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts.
authors.affiliation: Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Haidle
authors.affiliation: Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Kaleen K
authors.initials: KK
authors.lastname: Childers
authors.affiliation: Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Zabierek
authors.affiliation: Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Katz
authors.affiliation: Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Jewell
authors.affiliation: Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Altman
authors.affiliation: Department of In Vitro Sciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Szewczak
authors.affiliation: Department of Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Harsch
authors.affiliation: Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Mansuo
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Warren
authors.affiliation: Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
authors.affiliation: Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Hugh
authors.initials: H
authors.lastname: Nuthall
authors.affiliation: Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Matt G
authors.initials: MG
authors.lastname: Stanton
authors.affiliation: Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Ian W
authors.initials: IW
authors.lastname: Davies
authors.affiliation: Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Munoz
authors.affiliation: Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Northrup
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D011758:Pyrroles; D017346:Protein Serine-Threonine Kinases
keywords: Disposition study; In vitro–in vivo correlation; Kinase; MARK; Optimization; Pharmacokinetics; Physical properties