title: Discovery of triazines as selective PDE4B versus PDE4D inhibitors.
abstract: In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive 'closed' conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors.
authors.affiliation: Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, USA. Electronic address: thagen@niu.edu.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hagen
authors.affiliation: Tetra Discovery Partners LLC, Grand Rapids, MI, USA.
authors.forename: Xuesheng
authors.initials: X
authors.lastname: Mo
authors.affiliation: Beryllium, 7869 NE Day Rd. West, Bainbridge Island, WA 98110, USA.
authors.forename: Alex B
authors.initials: AB
authors.lastname: Burgin
authors.affiliation: Beryllium, 7869 NE Day Rd. West, Bainbridge Island, WA 98110, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fox
authors.affiliation: Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Tetra Discovery Partners LLC, Grand Rapids, MI, USA; Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA. Electronic address: mark@tetradiscovery.com.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Gurney
mesh_terms: D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010726:Phosphodiesterase Inhibitors; D014227:Triazines; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; C517376:PDE4D protein, human
keywords: Crystallography; PDE4 inhibitor; PDE4B; PDE4D; Triazine