Apremilast | PDE4 Inhibitor | Phosphodiesterase Inhibitor | Treatment for Active Psoriatic Arthritis | Treatment for Moderate-to-Severe Psoriasis

Apremilast [N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide] is a phthalimide-based, oral and potent small molecule inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE-4). It is under development for the treatment of psoriatic arthritis, psoriasis, ankylosing spondylitis, Behcet syndrome, atopic dermatitis, and rheumatoid arthritis [1, 2]. 

Apremilast has been approved by the USA FDA for the treatment of active psoriatic arthritis (PsA) and moderate-to-severe psoriasis (PsO). Apremilast has been approved by both the United States FDA and European Medicines Agency for treatment of PsA.

Psoriatic arthritis is a type of arthritis that causes pain and swelling of the joints and patches of scaly skin on some areas of the body. Apremilast is also used to treat moderate to severe plaque psoriasis, which is a skin disease with red patches and white scales that don't go away.

Apremilast: 2D and 3D Structure

Role of Phosphodiesterase (PDE)-4 in Inflammation

Cyclic adenosine monophosphate (cAMP) is a second messenger that plays a key role in the regulation of many biologic responses in humans, including inflammation, apoptosis, and lipid metabolism. This regulation is a result of the cAMP and protein kinase A (PKA) pathway, a common and versatile signaling mechanism in eukaryotic cells that is involved in the regulation of various cellular functions. Phosphodiesterase 4 (PDE4) is a key enzyme in the degradation of cyclic adenosine monophosphate and is centrally involved in the cytokine production of inflammatory cells, angiogenesis, and the functional properties of other cell types such as keratinocytes. PDE4 is widely expressed in hematopoietic cells (e.g. myeloid, lymphoid), nonhematopoietic cells (e.g. smooth muscle, keratinocyte, endothelial), and sensory/memory neurons. The four PDE4 genes (A, B, C, and D) exhibit distinct target and regulatory properties. Each of these genes can produce multiple protein products due to mRNA splice variants, resulting in approximately 19 different PDE4 proteins that fall into either short or long isoform categories. Long isoforms are differentiated from short isoforms by an additional upstream conserved region (UCR), which contains a PKA activation site [1].

Apremilast as Phosphodiesterase 4 Inhibitor

Apremilast, a novel small molecule inhibitor of Phosphodiesterase 4 (PDE4), has profound anti-inflammatory properties in animal models of inflammatory disease, as well as human chronic inflammatory diseases such as psoriasis and psoriatic arthritis. Apremilast blocks the synthesis of several pro-inflammatory cytokines and chemokines, such as tumor necrosis factor alpha, interleukin 23, CXCL9, and CXCL10 in multiple cell types. In contrast to the biologics, which neutralize pro-inflammatory mediators at the protein level, Apremilast modulates production of these mediators at the level of mRNA expression.

Apremilast also interferes with the production of leukotriene B4, inducible nitric oxide synthase, and matrix metalloproteinase and reduces complex inflammatory processes, such as dendritic cell infiltration, epidermal skin thickening, and joint destruction. As this novel PDE4 inhibitor interferes with several key processes of inflammation, it may emerge as a promising new drug for the treatment of chronic inflammatory diseases such as those of the skin and the joints [1].

Apremilast binds to the catalytic site of the PDE4 enzyme, thereby blocking cAMP degradation. Apremilast has an IC₅₀ of approximately 0.074 µM against PDE4. The K_i (affinity constant) of Apremilast for PDE4 is 68 nM. Apremilast is a partial competitive inhibitor of PDE4 based on Lineweaver-Burk analysis [2]. The compound did not demonstrate any marked PDE4 subfamily selectivity in the cAMP assays for PDE4 A4, B2, C2, and D3 with similar potencies at IC₅₀s ranging from 20 to 50 nM, thus not representing a PDE4 subtype-selective inhibitor. This explains why it has performed is better than Cilomilast and Rolipram in clinical trials. Apremilast does not induce central nervous system effects, such as lethargy and fatigue.

Apremilast inhibits the production of TNF-α (IC₅₀ = 0.11 µM), IFN-γ (IC₅₀ = 0.013 µM), and IL-12p70 (IC₅₀ = 0.12 µM), as well as the chemokines CXCL9 (MIG), CXCL10 (IP-10), and CCL4 (MIP1a) from human peripheral blood mononuclear cells [2]. One of the important features of apremilast activity in cells is that it retains its cellular potency in the whole-blood setting. Apremilast inhibits TNF-α production in whole blood (IC₅₀ = 0.11 µM) with potency similar to that in isolated cells. Clinically relevant concentrations of apremilast, based on the maximal plasma concentrations observed after the 20mg dose, are in the range of 450 nM (207.07 ng/ml) [1].

Apremilast , a novel, small molecule, represents the first oral therapy specifically developed for PsA [3].

Summary

Common name: Apremilast; CC-10004; CC10004; CC 10004; Otezla

Trademarks: Otezla

Molecular Formula: C22H24N2O7S

CAS Registry Number: 608141-41-9

CAS Name: (S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide

Molecular Weight: 460.50

SMILES:CCOC1=C(C=CC(=C1)C(CS(=O)(=O)C)N2C(=O)C3=C(C2=O)C(=CC=C3) NC(=O)C)OC

InChI Key: IMOZEMNVLZVGJZ-QGZVFWFLSA-N

InChI: InChI=1S/C22H24N2O7S/c1-5-31-19-11-14(9-10-18(19)30-3)17(12-32(4,28)29)24-21(26)15-7-6-8-16(23-13(2)25)20(15)22(24)27/h6-11,17H,5,12H2,1-4H3,(H,23,25)/t17-/m1/s1

Mechanism of Action: Phosphodiesterase 4 Inhibitor; Inhibition of TNF-alpha Production; PDE4 Inhibitor 

Indication: Anti-inflammatory Agents; Treatment of Psoriatic Arthritis; Treatment of Moderate to Severe Plaque Psoriasis 

Status: Launched 2014 (US, EU)

Chemical Class:  Isoindoles; phthalimides; small-molecules; sulfones;  thalidomide analog; ether containing; single enantiomer                    

Originator: Celgene Corporation

The activity of Apremilast is as follows:

IC₅₀ (TNF-α inhibition in LPS-stimulated hPBMC) = 0.077 uM (0.19, 0.37 uM)

IC₅₀ (TNF-α inhibition in LPS-stimulated WB) = 0.011 uM (0.44, ND uM)

IC₅₀ (Inhibition of PDE4 activity) = 0.074 uM (0.082, 0.61 uM)

The values in bracket correspond to activity of the racemic and R-enantiomer in the same assay.

Apremilast Synthesis

J Med Chem 2009, 52(6), 1522-1524: It is the earliest reported synthesis for Apermilast.

Tetrahedron: Asymmetry 2015, 26(10-11), 553-559: Reserachers report the use of catalytic asymmetric hydrogenation for the enantioselective synthesis of the key aminosulfone intermediate in order to identify a higher yielding and greener synthesis route. With >99% ee, and high yield, it appears to be the manufacturer's choice.

Identifications:

1H NMR (Estimated) for Apremilast

References:
1. Schett, G.; et. al. Apremilast: A Novel PDE4 Inhibitor in the Treatment of Autoimmune and Inflammatory Diseases. Ther Adv Musculoskelet Dis 2010, 2(5), 271-278. (FMO only)
2. Schafer, P.; et. al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol 2010, 159, 842-855. (FMO only)
3. Abdulrahim, H.; et. al. Apremilast : a PDE4 inhibitor for the treatment of psoriatic arthritis. Expert Opin Pharmacother 2015, 16(7), 1099-1108. (FMO only)

4. Man, H. W.; et. al. Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor. J Med Chem 2009, 52(6), 1522-1524. (FMO only)