Apremilast

Apremilast is a pivotal pharmaceutical intermediate and certified reference standard in the industrial synthesis and quality control of this first-in-class oral PDE4 inhibitor. The phthalimide core of Apremilast is synthesized through an acid-catalyzed condensation reaction between 3-acetamidophthalic anhydride and (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine. In quality control contexts, Apremilast and its related impurities—including Apremilast EP Impurity D, Impurity A, Impurity B, and various process-related byproducts—are essential analytical reference standards for impurity profiling, analytical method development, forced degradation studies, and quality control testing for generic manufacturers. As an orally active PDE4 inhibitor that modulates both innate and adaptive immune responses, Apremilast represents a significant therapeutic advance for inflammatory conditions. The phthalimide scaffold of Apremilast serves as a versatile platform for PDE4 inhibitor development, making Apremilast indispensable for pharmaceutical manufacturers developing generic versions and for analytical laboratories performing quality control testing.

 

Product Parameters

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Parameter	Specification
Product Name	Apremilast
CAS Number	608141-41-9

Molecular Formula	C₂₂H₂₄N₂O₇S
Molecular Weight	460.5 g/mol
Appearance	White to light yellow solid
Density	1.381 g/cm³
Boiling Point	741.3±60.0 °C at 760 mmHg
Melting Point	152-156 ℃
Storage Condition	Refrigerator

 

Preclinical Study

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1. In Vivo Activity

The study first transplanted normal human skin onto mice with severe combined immunodeficiency (SCID) and, after four weeks of transplantation, stimulated the skin using natural killer (NK) cells from psoriasis patients. Two weeks after NK cell injection, the mice were divided into three groups of seven each and administered either apustat or a placebo of cyclosporine orally. The rates of partial or complete histological recovery in the apustat group and the cyclosporine group were 57.1% and 42.9%, respectively. The results demonstrated that this drug effectively reduced epidermal thickness while significantly lowering concentrations of inflammation-related biomarkers such as TNF-α, intercellular adhesion molecule-1 (ICAM-1), and human leukocyte antigen DR (HLA-DR), with superior efficacy compared to the cyclosporine group.

 

2. Pharmacokinetics

The patient was administered apustat 20 mg/day, and pharmacokinetic parameters were monitored over 29 days. The half-life (t1/2) was 8.2 hours, the area under the concentration-time curve (AUC) was 1.799 μg/mL, the peak plasma concentration time (tmax) was 2 hours, the bioavailability was 10.4 L/h, the volume of distribution was 128 L, and the average steady-state plasma maximum concentration (Cmax) was 0.207 μg/mL (0.450 μmol/L). At this concentration, apustat effectively inhibited approximately 70% of THF-α production induced by lipopolysaccharide (LPS) in peripheral blood mononuclear cells (PBMCs).

 

 Mechanism Of Action

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This agent specifically targets PDE-4 to regulate the expression of pro-inflammatory and anti-inflammatory mediators in innate immune cells. In mononuclear dendritic cells, pro-inflammatory signals derived from the Toll-like receptor (TLR4) pathway activate the transcriptional nuclear factor kappa B (NF-κB) and promote the expression of pro-inflammatory mediators such as IL-23, TNF-α, and IFN-γ. Signals from G protein-coupled receptors (GPCRs), such as prostaglandin-binding proteins, activate adenylate cyclase (AC) by stimulating the α subunit of G protein (Gas), thereby generating cAMP. In leukocytes like macrophages and dendritic cells, cAMP is hydrolyzed by PDE-4 into AMP. As a PDE-4 inhibitor, apustatin increases intracellular cAMP levels, thereby activating cAMP-dependent protein kinase A (PKA) and simultaneously activating cyclic nucleotide-gated ion channels. PKA activation leads to phosphorylation of the cAMP response element (CRE) binding domain family within transcription factors and activates transcription factor 1 (ATF-1). In specific cells such as macrophages, these factors (e.g., IL-10) bind to CRE promoter sites to enhance gene expression. CRE-driven transcriptional activation further recruits coactivators such as CREB-binding protein (CBP) and homologous protein p300. CBPs and p300 derived from the NF-κB complex inhibit the transcriptional activity of NF-κB, thereby reducing the expression of NF-κB-dependent genes and leading to decreased levels of IL-23, TNF-α, and IFN-γ. The diminished inflammatory response results in reduced inflammatory infiltration of immune cells, along with decreased proliferation and activation of keratinocytes and synovial cells, which alleviates epidermal thickening in psoriasis and synovial damage in arthritis.

 

Drug Interaction

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1. Apustate is not an inhibitor of organic anion transporters (OAT) 1, OAT3, OCT2, or the organic anion transport peptides (OATP) 1B1 and OATP1B3, nor of breast cancer resistance protein (BCRP).

 

2. In vitro, although apustat is a substrate of P-glycoprotein (P-gp), its bioavailability in vivo exceeds 70%, and no significant interactions have been observed with ketoconazole (as studied in the DDI research involving CYP3A and P-gp inhibitors). Therefore, it does not inhibit systemic concentrations of P-gp.

 

3. No significant pharmacokinetic interactions have been observed when Apust (30 mg, qd, po) is co-administered with oral contraceptives, ketoconazole, or methotrexate.

 

4. Concomitant administration of the CYP450 inducer rifampin (600 mg, once daily, orally, for 15 days) with Aprest (30 mg, once daily, orally) resulted in a 72% reduction in Aprest's AUC and a 43% decrease in its Cmax.

 

Contact Us

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Need Apremilast for your PDE4 inhibitor development program, impurity profiling, or ANDA filing? Cosperpharm provides reliable supply, comprehensive documentation, and expert technical support—reach out to learn how we can help.