title: Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity.
abstract: Apremilast, an oral small molecule inhibitor of phosphodiesterase 4 (PDE4), is in development for chronic inflammatory disorders, and has shown efficacy in psoriasis, psoriatic arthropathies, and Behçet's syndrome. In March 2014, the US Food and Drug Administration approved apremilast for the treatment of adult patients with active psoriatic arthritis. The properties of apremilast were evaluated to determine its specificity, effects on intracellular signaling, gene and protein expression, and in vivo pharmacology using models of innate and adaptive immunity. Apremilast inhibited PDE4 isoforms from all four sub-families (A1A, B1, B2, C1, and D2), with IC50 values in the range of 10 to 100 nM. Apremilast did not significantly inhibit other PDEs, kinases, enzymes, or receptors. While both apremilast and thalidomide share a phthalimide ring structure, apremilast lacks the glutarimide ring and thus fails to bind to cereblon, the target of thalidomide action. In monocytes and T cells, apremilast elevated intracellular cAMP and induced phosphorylation of the protein kinase A substrates CREB and activating transcription factor-1 while inhibiting NF-κB transcriptional activity, resulting in both up- and down-regulation of several genes induced via TLR4. Apremilast reduced interferon-α production by plasmacytoid dendritic cells and inhibited T-cell cytokine production, but had little effect on B-cell immunoglobulin secretion. In a transgenic T-cell and B-cell transfer murine model, apremilast (5mg/kg/day p.o.) did not affect clonal expansion of either T or B cells and had little or no effect on their expression of activation markers. The effect of apremilast on innate immunity was tested in the ferret lung neutrophilia model, which allows monitoring of the known PDE4 inhibitor gastrointestinal side effects (nausea and vomiting). Apremilast significantly inhibited lung neutrophilia at 1mg/kg, but did not induce significant emetic reflexes at doses <30 mg/kg. Overall, the pharmacological effects of apremilast are consistent with those of a targeted PDE4 inhibitor, with selective effects on innate immune responses and a wide therapeutic index compared to its gastrointestinal side effects.
authors.affiliation: Department of Translational Development, Celgene Corporation, Summit, NJ, USA. Electronic address: pschafer@celgene.com.
authors.forename: P H
authors.initials: PH
authors.lastname: Schafer
authors.affiliation: Department of Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Parton
authors.affiliation: Department of Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: L
authors.initials: L
authors.lastname: Capone
authors.affiliation: Department of Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: D
authors.initials: D
authors.lastname: Cedzik
authors.affiliation: Department of Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: H
authors.initials: H
authors.lastname: Brady
authors.affiliation: Department of Biology, PharmAkea, San Diego, CA, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Evans
authors.affiliation: Department of Process Chemistry, Celgene Corporation, Summit, NJ, USA.
authors.forename: H-W
authors.initials: HW
authors.lastname: Man
authors.affiliation: GWM Consulting, Rancho Santa Fe, CA, USA.
authors.forename: G W
authors.initials: GW
authors.lastname: Muller
authors.affiliation: BioTheryX, Inc., Chappaqua, NY, USA.
authors.forename: D I
authors.initials: DI
authors.lastname: Stirling
authors.affiliation: Department of Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chopra
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005289:Ferrets; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D019169:Jurkat Cells; D008171:Lung Diseases / Q000188:drug therapy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058988:Phosphodiesterase 4 Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D014839:Vomiting / Q000517:prevention & control
chemical_list: D016207:Cytokines; D058988:Phosphodiesterase 4 Inhibitors; D013792:Thalidomide; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C505730:apremilast
keywords: Apremilast; Phosphodiesterase inhibitor; Preclinical drug evaluation; Psoriasis; Psoriatic arthritis; Spondyloarthropathies