title: Treatment of Skin Inflammation with Benzoxaborole Phosphodiesterase Inhibitors: Selectivity, Cellular Activity, and Effect on Cytokines Associated with Skin Inflammation and Skin Architecture Changes.
abstract: Psoriasis and atopic dermatitis are skin diseases affecting millions of patients. Here, we characterize benzoxaborole phosphodiesterase (PDE)-4 inhibitors, a new topical class that has demonstrated therapeutic benefit for psoriasis and atopic dermatitis in phase 2 or phase 3 studies. Crisaborole [AN2728, 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile], compd2 [2-ethoxy-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)nicotinonitrile], compd3 [6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-(2-isopropoxyethoxy)nicotinonitrile], and compd4 [5-chloro-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-((4-oxopentyl)oxy)nicotinonitrile] are potent PDE4 inhibitors with similar affinity for PDE4 isoforms and equivalent inhibition on the catalytic domain and the full-length enzyme. These benzoxaboroles are less active on other PDE isozymes. Compd4 binds to the catalytic domain of PDE4B2 with the oxaborole group chelating the catalytic bimetal and overlapping with the phosphate in cAMP during substrate hydrolysis, and the interaction extends into the adenine pocket. In cell culture, benzoxaborole PDE4 inhibitors suppress the release of tumor necrosis factor-α, interleukin (IL)-23, IL-17, interferon-γ, IL-4, IL-5, IL-13, and IL-22, and these cytokines contribute to the pathologic changes in skin structure and barrier functions as well as immune dysregulation in atopic dermatitis and psoriasis. Treatment with compd3 or N(6),2'-O-dibutyryladenosine 3',5'-cyclic monophosphate increases cAMP response element binding protein phosphorylation in human monocytes and decreases extracellular signal-regulated kinase phosphorylation in human T cells; these changes lead to reduced cytokine production and are among the mechanisms by which compd3 blocks cytokine release. Topical compd3 penetrates the skin and suppresses phorbol myristate acetate-induced IL-13, IL-22, IL-17F, and IL-23 transcription and calcipotriol-induced thymic stromal lymphopoietin expression in mouse skin. Skin thinning is a major dose-limiting side effect of glucocorticoids. By contrast, repeated application of compd3 did not thin mouse skin. These findings show the potential benefits and safety of benzoxaborole PDE4 inhibitors for the treatment of psoriasis and atopic dermatitis.
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California cdong@anacor.com.
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Virtucio
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Olga
authors.initials: O
authors.lastname: Zemska
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Grober
authors.initials: G
authors.lastname: Baltazar
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Yasheen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Diogo
authors.initials: D
authors.lastname: Baia
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Shannon
authors.initials: S
authors.lastname: Jones-Iatauro
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Holly
authors.initials: H
authors.lastname: Sexton
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Shamra
authors.initials: S
authors.lastname: Martin
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Joshua
authors.initials: J
authors.lastname: Dee
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Mak
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Maliwan
authors.initials: M
authors.lastname: Meewan
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rock
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Akama
authors.affiliation: Anacor Pharmaceuticals, Inc., Palo Alto, California.
authors.forename: Kurt
authors.initials: K
authors.lastname: Jarnagin
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001896:Boron Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020134:Catalytic Domain; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D001896:Boron Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D058988:Phosphodiesterase 4 Inhibitors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C543085:crisaborole; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse