title: Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center.
abstract: We have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-α, IL-2, IFN-γ, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors.
authors: Anacor Pharmaceuticals Inc., Palo Alto, CA 94303, USA. yfreund@anacor.com
authors: Yvonne R
authors: YR
authors: Freund
authors: Tsutomu
authors: T
authors: Akama
authors: M R K
authors: MR
authors: Alley
authors: Joana
authors: J
authors: Antunes
authors: Chen
authors: C
authors: Dong
authors: Kurt
authors: K
authors: Jarnagin
authors: Richard
authors: R
authors: Kimura
authors: James A
authors: JA
authors: Nieman
authors: Kirk R
authors: KR
authors: Maples
authors: Jacob J
authors: JJ
authors: Plattner
authors: Fernando
authors: F
authors: Rock
authors: Rashmi
authors: R
authors: Sharma
authors: Rajeshwar
authors: R
authors: Singh
authors: Virginia
authors: V
authors: Sanders
authors: Yasheen
authors: Y
authors: Zhou
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001896:Boron Compounds / Q000737:chemistry* / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008670:Metals / Q000737:chemistry; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001896:Boron Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016207:Cytokines; D007527:Isoenzymes; D008670:Metals; D010726:Phosphodiesterase Inhibitors; D011994:Recombinant Proteins; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; C543085:crisaborole