Definition
ChEBI: A member of the class of isoindoles that is isoindole-1,3-dione substituted at position 4 by an acetamido group and at position 1 by a 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl group. Used for treatment of psoriatic arthritis.
Clinical Use
Treatment of active psoriatic arthritis (PsA) and
moderate to severe chronic plaque psoriasis (PSOR)
Synthesis
Dimethyl sulfone was first subjected to n-butyllithium in
tetrahydrofuran (THF) prior to exposure to commercially available
3-ethoxy-4-methoxybenzonitrile (15) at low temperature to afford
enamine 16 in 83% yield, presumably as a single isomer enamine
possessing the E-configuration. After considerable studies conducted
by researchers at Celgene regarding the reduction of this
enamine and alternative substrates, enamine 16 was reduced
under asymmetric hydrogenation conditions consisting of [Rh
(COD)2]OTf and (S,R)-t-Bu Josiphos in trifluoroethanol (TFE) at
50 ?? under 90 psi of hydrogen pressure. Immediate exposure of
the product to N-acetyl-L-leucine in methanol afforded the corresponding
benzylamine salt 18 in 80% yield and more than 99%
enantiomeric excess (ee). Finally, compound 18 was condensed
with commercially available N-(phthalimid-3-yl)acetamide (19)
in refluxing acetic acid to provide apremilast (III) in 83% yield
and 99.4% ee.
Overdosage
Apremilast was studied in healthy subjects at a maximum total daily dose of 100 mg (given as 50 mg twice daily) for 4.5 days without evidence of dose limiting toxicities. In case of an overdose, it is recommended that the patient is monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment is instituted. In the event of overdose, symptomatic and supportive care is advised.
Enzyme inhibitor
This thalidomide-like psoriasis drug (FW = 460.50 g/mol; CAS 608141-41-9; Solubility: 90 mg/mL DMSO; <1 mg/mL H2O), also known as CC-10004, Otezla? and N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methyl-sulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, is a potent, orally active phosphodiesterase inhibitor that targets phosphodiesterase PDE4 (IC50 = 74 nM), itself a proinflammatory mediator, and TNF-α, IC50 = 77 nM. Apremilast inhibits PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon-γ and tumor necrosis factor-α (TNF-α), and interleukins IL-2, IL-12 and IL- 23 from human rheumatoid synovial membrane cultures. Apremilast significantly reduces clinical scores in both murine models of arthritis over a ten-day treatment period and maintains healthy joint architecture in a dose-dependent manner. Unlike rolipram, however, apremilast demonstrated no adverse behavioral effects in na?ve mice. Otezla is specifically indicated by the Food & Drug Administration for the treatment of patients with moderate to severe plaque psoriasis who are typically candidates for phototherapy or systemic therapy. That said, the specific mechanism(s) for therapeutic action in psoriatic arthritis patients and psoriasis patients is unclear.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin
- avoid.
Antidepressants: concentration possibly reduced by
St John’s wort - avoid.
Antiepileptics: concentration possibly reduced
by carbamazepine, fosphenytoin, phenobarbital,
phenytoin and primidone - avoid.
Metabolism
Apremilast is extensively metabolised by both CYP
and non-CYP mediated pathways including oxidation,
hydrolysis, and conjugation, suggesting inhibition of a
single clearance pathway.
After oral administration of radiolabelled apremilast,
about 3% and 7% of the radioactive dose is recovered as
apremilast in urine and faeces, respectively.
Mode of action
Apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. These pro- and anti-inflammatory mediators have been implicated in psoriatic arthritis and psoriasis.
