Structure guided design of a series of selective pyrrolopyrimidinone MARK inhibitors.
The initial structure activity relationships around an isoindoline uHTS hit will be described. Information gleaned from ligand co-crystal structures allowed for rapid refinements in both MARK potency and kinase selectivity. These efforts allowed for the identification of a compound with properties suitable for use as an in vitro tool compound for validation studies on MARK as a viable target for Alzheimer's disease.
Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: jason_katz2@merck.com.
Jason D
JD
Katz
Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Andrew
A
Haidle
Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Kaleen K
KK
Childers
Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Anna A
AA
Zabierek
Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
James P
JP
Jewell
Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Yongquan
Y
Hou
Department of Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Michael D
MD
Altman
Department of In Vitro Sciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Alexander
A
Szewczak
Department of Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Dapeng
D
Chen
Department of Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Andreas
A
Harsch
Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Mansuo
M
Hayashi
Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Lee
L
Warren
Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Michael
M
Hutton
Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Hugh
H
Nuthall
Department of Structural Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Hua-Poo
HP
Su
Department of Structural Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Sanjeev
S
Munshi
Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Matt G
MG
Stanton
Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Ian W
IW
Davies
Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Ben
B
Munoz
Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Alan
A
Northrup
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D011758:Pyrroles; C105547:MARK1 protein, human; C094670:MARK2 protein, human; C111833:MARK3 protein, human; C483047:MARK4 protein, human; D017346:Protein Serine-Threonine Kinases
Alzheimer’s disease; Kinase; MARK; Pyrrolopyrimidinone; Tau