title: Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties.
abstract: Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer's disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility.
authors: Discovery Chemistry, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: David L
authors: DL
authors: Sloman
authors: Discovery Chemistry, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Njamkou
authors: N
authors: Noucti
authors: Chemistry Modeling and Informatics, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Michael D
authors: MD
authors: Altman
authors: Drug Metabolism and Pharmacokinetics, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Dapeng
authors: D
authors: Chen
authors: Drug Metabolism and Pharmacokinetics, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Andrea C
authors: AC
authors: Mislak
authors: CNS Pharmacology, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Alexander
authors: A
authors: Szewczak
authors: CNS Pharmacology, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Mansuo
authors: M
authors: Hayashi
authors: CNS Pharmacology, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Lee
authors: L
authors: Warren
authors: Core Pharmacology, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Tammy
authors: T
authors: Dellovade
authors: Core Pharmacology, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Zhenhua
authors: Z
authors: Wu
authors: Neuroscience Drug Discovery, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Jacob
authors: J
authors: Marcus
authors: Pharmaceutical Research and Development, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Deborah
authors: D
authors: Walker
authors: Structural Biology, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Hua-Poo
authors: HP
authors: Su
authors: Structural Biology, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Suzanne C
authors: SC
authors: Edavettal
authors: Structural Biology, 770 Sumneytown Pike, West Point, PA 19486, United States.
authors: Sanjeev
authors: S
authors: Munshi
authors: Neuroscience Drug Discovery, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Michael
authors: M
authors: Hutton
authors: Neuroscience Drug Discovery, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Hugh
authors: H
authors: Nuthall
authors: Discovery Chemistry, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
authors: Matthew G
authors: MG
authors: Stanton
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008970:Molecular Weight; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D012995:Solubility
chemical_list: D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; C111833:MARK3 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Alzheimer’s disease; Amine basicity; Fluorine; Kinase; MARK