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.

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

“…For example, IMiDs are effective inhibitors of TLR4-induced TNFα, IL12p40, and IFNβ in Cereblon-deficient mice (5). Moreover, thalidomide analogs that lack the Cereblon binding moiety, such as apremilast, retain their inhibitory effect on TLR-induced cytokine production (8).…”

Apremilast: A Review in Psoriasis and Psoriatic Arthritis

“…In vitro, apremilast displayed potent inhibition of several representative PDE4 isoforms (half maximal inhibitory concentrations 14-118 nmol/L), but displayed no significant inhibition of other PDEs, kinases or cell surface receptors [9,10]. Inhibition of PDE4 by apremilast in peripheral blood mononuclear cells (PBMCs) elevated levels of prostaglandin-induced cAMP (half maximal effective concentration 1.4 lmol/L) [9].…”

Current views on the pharmacotherapy of psoriatic arthritis

“…Кроме того, апремиласт ингибирует экспрессию провоспа-лительных цитокинов и увеличивает экспрессию противо-воспалительных медиаторов, таких как ИЛ10 [51,52].…”