Apremilast
Apremilast
CAS: 608141-41-9
Molecular Formula: C22H24N2O7S
Apremilast - Names and Identifiers
| Name | Apremilast |
| Synonyms | Apster CS-1055 CC10004 CC 10004 CC10004 CC-10004 CC 10004 Apremilast APREMILAST Unii-up7qbp99pn ApreMilast,CC-10004 (S)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione (S)-4-Acetylamino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione (S)-N-(2-(1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide |
| CAS | 608141-41-9 |
| EINECS | 807-237-6 |
| InChI | N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide |
Apremilast - Physico-chemical Properties
| Molecular Formula | C22H24N2O7S |
| Molar Mass | 460.5 |
| Density | 1.381 |
| Melting Point | 152-156°C |
| Boling Point | 741.3±60.0 °C(Predicted) |
| Solubility | Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly, Heated) |
| Appearance | Solid |
| Color | White to Pale Yellow |
| pKa | 14.01±0.20(Predicted) |
| Storage Condition | Refrigerator |
| In vitro study | Apremilast inhibits PDE4 more effectively than other PDE-family cAMP or cGMP hydrolases. Apremilast acts on a wide variety of cell types, has a broad anti-inflammatory activity, inhibits the production of TNF-α,IL-12 and IL-23, and the response of NK and keratinocytes. Apremilast inhibits zymosan-induced PMN production in IL-8 with an IC50 of 94 nM. Apremilast inhibited the expression of PMN CD18 and CD11b induced by fMLF with IC50 of 390 nM and 74 nM respectively, and inhibited the adhesion of PMN and HUVECs induced by fMLF with IC50 of 150 nM. Apremilast inhibits the production of keratinocyte TNF-α, and it was found that Apremilast had no effect on keratinocyte viability by measuring intracellular ATP levels. |
| In vivo study | In the presence of human microsomes (t1/2>60 min), Apremilast is stable. 90% of the protein is bound in human plasma. Oral and intravenous administration to female rats showed that Apremilast has good pharmacokinetics, low clearance, moderate volume distribution, and an oral bioavailability of 64%. Apremilast treated the rat model of inhibition of TNF-α induced by LPS in vivo, and the ability of Apremilast to inhibit TNF-α was detected, and the ED50 was determined to be 0.03 mg/kg. Apremilast treated another LPS-induced neutrophil rat model with ED50 of 0.3 mg/kg to 0.9 mg/kg. |
Apremilast - Reference
| Reference Show more | 1. [IF=8.739] Yanhong Pan et al."The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation."Brit J Pharmacol. 2021 Dec;178(24):4907-4922 |
Apremilast - Introduction
Apremilast (CC-10004) is an orally biopotent PDE4 and TNF-α inhibitor with IC50 of 74 nM and 77 nM, respectively.
Last Update：2022-10-16 17:27:01
Apremilast - Reference Information
| Overview | apremilast is developed by Celgene biotechnology, USA, on March 21, 2014, it was approved by the U. S. Food and Drug Administration (FDA) for the treatment of active psoriatic arthritis (PsA) in adults. |
| medicinal product overview | alias: aprest: N/A,CC-10004 English name: apremilast trade name: Otezla product name: S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-4-acetylaminoisoindoline -1, 3-dione chemical name:-N-[2-[1(S)]-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-1,3-dioxo-2, 3-dihydroxy-1h-isoindol-4-yl] acetamide Molecular formula: C22H24N2O7S Molecular Weight: 460.5 original research company: Celgene pharmacological classification: phosphodiesterase -4(PDE-4) and tumor necrosis factor-α(TNF-α) dual inhibitors indication: psoriasis, psoriatic arthritis current stage: Phase III clinical route of administration: Oral Figure 1-structural formula of aprexed |
| psoriasis treatment drug | apremilast is an oral, the selective phosphodiesterase 4(PDE4) inhibitor, trade name Otezla, is the first and only FDA-approved PDE4 inhibitor for the treatment of plaque psoriasis, for the treatment of adult patients with moderate to severe Plaque Psoriasis suitable for phototherapy and systemic therapy. on March 21, 2014, the US FDA approved Otezla (apremilast) for the treatment of adults with active psoriatic arthritis (PsA). Most people develop psoriasis before being diagnosed with PsA. Joint pain, stiffness and swelling are the main signs and symptoms of PsA. Drugs currently approved for PsA include glucocorticoids, tumor necrosis factor (TNF) blockers, and interleukin-12/interleukin-23 inhibitors. Otezla is a phosphodiesterase-4 (PDE-4) inhibitor whose safety and efficacy are based on three Phase 3 trials involving 1493 patients with active psoriatic arthritis. Otezla-treated patients showed improvements in PsA signs and symptoms compared with placebo patients, with ACR20 response rates of 32-41% in the apremilast group and 18-19% in the placebo group. Aprast is an oral antirheumatic drug with a completely new mechanism of action, which is different from the anti-TNF monoclonal antibody currently used in clinical practice. EvaluatePharma predicts sales of US $1.219 billion in 2018. patients treated with Otezla should have their weight monitored regularly by a health care professional. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated and treatment discontinuation should be considered. Patients treated with Otezla had an increased risk of depression compared with those treated with placebo. In clinical trials, the most common side effects were Diarrhea, Nausea and Head Pain in Otezla patients. Otezla is produced by thre genes, Inc., based in Summit, ban, New Jersey. Figure 1 shows the aprester tablets (trade name: Otezla) produced by Celgene, USA. |
| preclinical studies | 1, in vivo activity studies first, normal human skin was transplanted into beige severe combined immunodeficiency (SCID) mice, skin is stimulated with natural killer cells (NK cells) from patients with psoriasis. Two weeks after the injection of NK cells, the mice were divided into 3 groups, 7 mice in each group, and the mice were orally administered with apreast and cyclosporine placebo respectively. The rates of partial or complete recovery in histological features were 57.1% and 42.9% in the aprast and cyclosporine groups, respectively. The results show that the drug can effectively reduce the thickness of the epidermis, and can effectively reduce the TNF-α, intracellular adhesion molecule -1(ICAM-1) and human leukocyte antigen DR(HLA-DR). Such as the concentration of inflammation-related substances, its pharmacodynamic effect is better than that of cyclosporine group. 2. Pharmacokinetics The patients were treated with po of aprexast 20 mg/d, and the pharmacokinetic parameters were observed for 29 days. The Half-Life (t1/2) was 8.2 h, the area under the curve was 1.799 μg/mL, and the time to peak (tmax) was 2 h, bioavailability was 10.4 L/h, volume of distribution was 128 L, mean steady-state maximum plasma concentration (Cmax) was 0.207 μg/mL(0.450 μmol/L), at this concentration, aprilast effectively inhibits about 70% of THF-α production by lipopolysaccharide (LPS) induced by peripheral blood mononuclear cells (PBMC). |
| clinical evaluation | compared with similar drugs, aprexed (trade name: Otezla) has the following advantages: 1, it can inhibit the production of a variety of pro-inflammatory mediators (PDE-4, TNF-α, IL-2, interferon r, leukotriene, NO synthase) and play an anti-inflammatory role. 2, phosphodiesterase 4(PDE4) selective inhibitor, in addition to the approval for use in psoriatic arthritis, 2014, FDA approved for phototherapy or systemic therapy in patients with moderate to severe treatment of plaque psoriasis. Is the first and only PDE4 inhibitor approved for the treatment of plaque psoriasis. 3. Clinical trials have shown that apreter can reduce erythema, thickening and desquamation in patients with moderate to severe plaque psoriasis. 4, clinical trials have proved that aprexed is well tolerated, less adverse reactions, clinical trials Otezla treatment group compared with placebo, patients showed improvement in PsA signs and symptoms, including tenderness, swelling of the joints and body function. 5, other indications are doing clinical, such as rheumatoid arthritis, mandatory myelitis, Behcet's disease, ulcerative colitis, etc. The market potential is large. [registration classification] According to the requirements of the registration management method, the raw material is 3.1 and the tablet is 3.1. [dosage forms and specifications] raw materials and tablets, 10mg,20mg,30mg. [indication] for the treatment of active psoriatic arthritis in adult patients. This information was edited by chemical book Xiaonan (2015-08-14). |
| relevant patent information of aprst | relevant patent information of aprst: compound: WO0025777, no patent in China. use: ZL03811093.8/ZL200610137407.4,2023.03.20. crystal form: CN200880129462.6,2008.03.27. |
| preparation method | 1. Using 3-ethoxy-4-methoxybenzonitrile (1) as raw material, reaction with dimethyl sulfoxide (pretreated with n-butyl lithium in tetrahydrofuran) in tetrahydrofuran to give the enamine derivative (2), subsequent reduction by asymmetric hydrogenation in trifluoroethanol solution at 50 °c gives the desired S-type amine (3). N-acetyl-L-leucine is added to the methanol solution of 3 to obtain the corresponding salt (4), and finally with the benzofuran derivative (5) in acetic acid reflux, aprest was obtained by condensation reaction. 5 can be prepared from 3-nitrophthalic acid by Nitro reduction, and then acetic anhydride acylation reaction. The synthesis route is as follows: 2, with 3-ethoxy-4-methoxybenzaldehyde as raw material, formation of 3-ethoxy-4-methoxybenzaldehyde imine in the hexamethyldisilyllithium tetrahydrofuran solution, then with dimethyl sulfone, 1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethanone (1) was obtained by reacting a diethyl ether solution of n-butyl lithium and boron trifluoride at 78 ° C; methanol as solvent, compound 1 and N-acetyl-L-leucine by chemical separation of S-isomer compound (2); Compound 2 and 3-n-acetylamino phthalic anhydride in acetic acid reflux, the target compound, apast, was obtained by condensation reaction. The synthetic route is as follows: |
| mechanism of action | This product specifically targets PDE-4 to regulate the expression of pro-inflammatory and anti-inflammatory mediators in innate immune cells. In monocyte nuclear dendritic cells, the activation of nuclear factor kappa B(NF-κB) and the expression of pro-inflammatory mediators are caused by pro-inflammatory signals derived from Toll-like receptor (TLR4) pathway, such as IL-23, TNF-α and IFN-g. Signals derived from G protein-coupled receptors (GPCRs) such as prostaglandin-binding proteins activate adenylate cyclase (AC) by stimulating the G protein alpha subunit (Gas), thereby producing cAMP. In leukocytes such as macrophages and dendritic cells, cAMP is PDE-4 hydrolyzed to AMP. As A PDE-4 inhibitor, aprast increases intracellular cAMP levels, thereby activating cAMP-dependent protein kinase A(PKA) and cyclic nucleotide-gated ion channels, activation of PKA results in phosphorylation of the cAMP response element (CRE) binding family of transcription factors, while activating transcription factor 1(ATF-1). In certain cells, such as macrophages, these factors such as IL-10 will be bound to the CRE gene promoter binding site to increase the expression of cell genes, CRE-driven transcriptional activation aggregates co-activators such as CREB binding protein (CBP), the homologous protein p300, etc. CBP and p300 from the NF-κB collection inhibited the transcriptional activity of NF-κB and decreased the expression of NF-κB-dependent genes, resulting in a decrease of IL-23, TNF-α and IFN-g. A reduced response to inflammation reduces inflammatory infiltration of immune cells while reducing proliferative activation of keratinocytes and synoviocytes, reducing epidermal thickening in psoriasis, and synovial damage in arthritis. |
| safety | 1. Depression when the drug is used, the adverse reactions of depression are related to the dose increase. Therefore, patients with a history of depression and/or Suicide thoughts or behaviors should carefully weigh the risks and benefits of treatment before using this product. Patients, caregivers, and family members should be informed of the need for depression, Suicide thoughts, or other mood changes to occur or worsen; If such a situation occurs, should be timely treatment and careful evaluation of whether to continue to use this product. 2. Weight loss patients treated with this product should regularly monitor their weight. If there is unexplained or clinically significant weight loss, it should be evaluated and considered to terminate the use of this product. 3. Adverse reactions The common adverse reactions were Nausea, Diarrhea, Head Pain, Upper Respiratory Infections, nasopharyngitis and upper abdominal pain, etc., most of which were mild or moderate, most of which disappeared within 4 weeks. |
| biological activity | Apremilast (CC-10004) is an orally bioavailable inhibitor of PDE4 and TNF-α, the IC50 was 74 nM and 77 nM, respectively. |
| drug interaction | 1, apreter is not an organic anion transporter (OAT)1,OAT3, oct 2 and inhibitors of organic anion transport polypeptide (OATP)1B1 and OATP1B3 or breast cancer resistance protein (BCRP). 2, in vitro, apreter is a P-glycoprotein (P-gp) substrate, but in vivo Bioavailability> 70%, no significant interaction was found with ketoconazole (DDI study CYP3A and P-gp inhibitors). Thus, the systemic concentration was not inhibited by P-gp. 3. No significant pharmacokinetic interaction was observed with aprexed (30 mg,qd,po) administered concomitantly with oral contraceptives, ketoconazole or methotrexate. 4. The CYP 450 inducer rifampicin (600 mg,qd,po, 15 d in total) and aprexed (30 mg,qd,po) were administered at the same time, the results resulted in a 72% and 43% reduction in AUC and Cmax for apreter, respectively. |
| reference material | [1] Chen Jian Super compiler. apremilast. Chinese Journal of Medicinal Chemistry. 2014. 24(5). [2] Zhao Qian, Sun Yue, Shi Yu, et al. A phosphodiesterase -4 inhibitor of apreast [J]. Modern medicine and clinic, 2014, 29(4): 428-433. [3] Wu Aiping, Zhang Zhiye, Wang Li. Pharmacological action and clinical evaluation of a new drug aprexed for the treatment of psoriatic arthritis. New drug review and forum. Chinese Journal of new drugs, 2015, 24 (9). description: the information given is limited, mainly summarizes the preparation method, pharmacological mechanism and safety of the literature, for its application in medicine to lay the foundation. |
| Use | is indicated for the treatment of adult patients with active psoriatic arthritis. |
| toxic substance data | information provided by: pubchem.ncbi.nlm.nih.gov (external link) |
Last Update：2024-04-09 20:52:54
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