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-α Inhibitor

Man, Hon‐Wah; Schäfer, Peter; Wong, Lu Min; Patterson, Rebecca T.; Corral, Laura G.; Raymon, Heather K.; Blease, Kate; Leisten, Jim; Shirley, Michael A.; Tang, Yang; Babusis, Darius; Chen, Roger; Stirling, D. I.; Muller, George W.

doi:10.1021/jm900210d

Cited by 153 publications

(75 citation statements)

References 16 publications

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“…Using apremilast causes inhibition of PDE4 enzyme and as a result, degradation of cAMP is prevented. This causes increased levels of cAMP in PDE4-expressing cells, which prevents synthesis of many pro-inflammatory markers including TNF-a, IFN-g, interleukins and chemokines (e.g., CXCL9, CXCL10 and CCL4) [37,43]. Elevation of cAMP in human keratinocytes after use of PDE4 inhibitors such as apremilast might explain some of the pathophysiological response of psoriasis to these medications.…”

Section: Drug Name (Generic)mentioning

confidence: 99%

Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis

Abdulrahim¹,

Thistleton²,

Adebajo³

et al. 2015

Expert Opinion on Pharmacotherapy

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Section: Drug Name (Generic)mentioning

confidence: 99%

Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis

Abdulrahim¹,

Thistleton²,

Adebajo³

et al. 2015

Expert Opinion on Pharmacotherapy

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“…In addition, the structure of 35 in complex with TNF-α dimer was solved [92]. Celgene Corporation recently developed apremilast ( 36 , Figure 8) as an orally active dual phosphodiesterase-4 (PDE4) and TNF-α inhibitor that could be used to treat the autoimmune disorder psoriasis [93]. Compound 36 , has a dihydroisoindole ring template and is an ( S )-enantiomer, whereas the corresponding ( R ) enantiomer of 36 was 5-fold less potent.…”

Section: Tnf-α Inhibitorsmentioning

confidence: 99%

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development

2010

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Ever since the discovery of aspirin, small molecule therapeutics have been widely prescribed to treat inflammation and pain. Aspirin and several small molecule NSAIDs are known to inhibit the enzymes cyclooxygenase-1 (COX-1) and -2 (COX-2). Despite the success of NSAIDs to treat inflammatory disorders, the development of a clinically useful small molecule NSAIDs with decreased side effect profiles is an ongoing effort. The recent discovery and development of selective COX-2 inhibitors was a step toward this direction. Emerging trends are represented by the progress in the development of hybrid agents such as nitric oxide donor-NSAIDs (NO-NSAIDs) and dual COX/lipoxygenase (LOX) inhibitors. This review focuses on the recent advances in the rational design of small molecule NSAIDs in therapy.

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“…Apremilast ((S)-N-(2-[1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonylethyl]-1,2-dioxo-2,3-dihydro-1H-isoindol-4-yl) acetamide) is a phosphodiester 4 (PDE4) inhibitor [194]. Elevated tumor necrosis factor-α (TNF-α) levels are associated with several inflammatory diseases.…”

Section: Uveitismentioning

confidence: 99%

Recent Patents on Emerging Therapeutics for the Treatment of Glaucoma, Age Related Macular Degeneration and Uveitis

Vadlapudi¹,

Patel²,

Cholkar³

et al. 2012

BIOMENG

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Advancements in the field and rising interest among pharmaceutical researchers have led to the development of new molecules with enhanced therapeutic activity. Design of new drugs which can target a particular pathway and/or explore novel targets is of immense interest to ocular pharmacologists worldwide. Delivery of suitable pharmacologically active agents at proper dose (within the therapeutic window) to the target tissues without any toxicity to the healthy ocular tissues still remain an elusive task. Moreover, the presence of static and dynamic barriers to drug absorption including the corneal epithelium (lipophilic), corneal and scleral stroma (hydrophilic), conjunctival lymphatics, choroidal vasculature and the blood-ocular barriers also pose a significant challenge for achieving therapeutic drug concentrations at the target site. Although many agents are currently available, new compounds are being introduced for treating various ocular diseases. Deeper understanding of the etiology and complex mechanisms associated with the disease condition would aid in the development of potential therapeutic candidates. Novel small molecules as well as complex biotechnology derived macromolecules with superior efficacy, safety and tolerability are being developed. Therefore, this review article provides an overview of existing drugs, treatment options, advances in emerging therapeutics and related recent patents for the treatment of ocular disorders such as glaucoma, age related macular degeneration (AMD) and uveitis.

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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-α Inhibitor

Cited by 153 publications

References 16 publications

Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis

Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development

Recent Patents on Emerging Therapeutics for the Treatment of Glaucoma, Age Related Macular Degeneration and Uveitis

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