Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis

Abdulrahim, Hunar; Thistleton, Samuel; Adebajo, Adewale; Shaw, Tim; Edwards, Christopher J; Wells, Alvin F.

doi:10.1517/14656566.2015.1034107

Cited by 36 publications

(16 citation statements)

References 65 publications

(70 reference statements)

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“…PKA is composed of two separate subunits, namely, catalytic and regulatory subunits. Upon cAMP elevation, the free catalytic subunit is activated and subsequently affects a wide range of cytoplasmic and nuclear transcriptional factors, including CREB, CREM, and ATF‐1, which contribute to the anti‐inflammation effects in inflammatory conditions (Abdulrahim et al, ). This bioactivity was confirmed in our study on RAW264.7 cells and BMDMs using a PKA inhibitor or siRNA to silence the catalytic subunit of PKA.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of phosphodiesterase‐4 attenuates murine ulcerative colitis through interference with mucosal immunity

Chen

Feng

et al. 2019

British J Pharmacology

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Background and Purpose Ulcerative colitis (UC) is an aetiologically refractory inflammatory disease, accompanied by dysfunction of the epithelial barrier and intestinal inflammation. Phosphodiesterase‐4 (PDE4) serves as an intracellular proinflammatory enzyme, hydrolyzing and inactivating cAMP. Though PDE4 inhibitors have been approved for pulmonary and dermatological diseases, the role of PDE4 inhibition in modulating mucosal immunity in the intestine remains ill‐defined. This study was designed to explore whether PDE4 inhibition by apremilast exerts protective effects in dextran sulfate sodium‐induced murine UC. Experimental Approach Intestinal inflammation and disease severity were evaluated by morphological, histopathological and biochemical assays, and in vivo imaging. Expression of inflammatory mediators, components of PDE4‐mediated pathways in colon and macrophages were determined using quantitative real‐time PCR, ELISA, Luminex assay, immunostaining, or western blotting, along with siRNA knockdown. Immune cells in mesenteric lymph nodes and colonic lamina propria were analysed by flow cytometry. Key Results Apremilast attenuated clinical features of UC, suppressing microscopic colon damage, production of inflammatory mediators, oxidative stresses, and fibrosis. Apremilast also promoted epithelial barrier function and inhibited infiltration of immune cells into inflamed tissues, through decreasing expression of chemokines and chemokine receptors. Furthermore, in UC, PDE4A, PDE4B, and PDE4D were highly expressed in colon. Apremilast not only inhibited PDE4 isoform expression but also activated PKA–CREB and Epac‐Rap1 pathways and subsequently suppressed MAPK, NF‐κB, PI3K–mTOR, and JAK–STAT–SOCS3 activation. Conclusion and Implications Inhibition of PDE4 by apremilast protected against UC, by interfering with mucosal immunity. These findings represent a promising strategy for regulating intestinal inflammation.

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Section: Discussionmentioning

confidence: 99%

Inhibition of phosphodiesterase‐4 attenuates murine ulcerative colitis through interference with mucosal immunity

Chen

Feng

et al. 2019

British J Pharmacology

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“…Absorption: apremilast, orally administered, is absorbed with an absolute bioavailability of ~73%, contribution from CYP1A2 and CYP2A6 [38,39].…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

Pharmacodynamic assessment of apremilast for the treatment of moderate-to-severe plaque psoriasis

Bianchi

Duca

Romanelli

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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“…Since cAMP has been found to be of great importance in a variety of cellular functions, PDE4 may be a good target for inflammatory diseases (Martinez & Gil, 2014;Mulhall, Droege, Ernst, Panos, & Zafar, 2015) and central nervous system (CNS) disorders (Heckman, Wouters, & Prickaerts, 2015;Prickaerts, Heckman, & Blokland, 2017). Many natural and synthetic compounds have been reported as PDE4 inhibitors, and three selective PDE4 inhibitors have been brought to market: roflumilast (Rabe, 2011;Tashkin, 2014), apremilast (Abdulrahim et al, 2015), and crisaborole (Paton, 2017; Figure 1). Furthermore, many PDE4 inhibitors with antidepressant and memory-enhancing activity have been confirmed in preclinical models or early stage clinical trials (Bolger, 2017;Heckman et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study

et al. 2018

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Phosphodiesterase 4 (PDE4) inhibitors with potential activities for CNS disorders provide a new therapeutic strategy for depression. To discover PDE4 inhibitors with anti‐neuroinflammation activities, reliable three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models on our previous reported catecholic PDE4 inhibitors was built with a statistically significant cross‐validated coefficient (q2), conventional coefficient (r2), and good predictive capabilities based on the molecular docking results, using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods. Based on the analysis of CoMFA and CoMSIA contour maps, a series of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl) acetonitriles 16a–i was designed and synthesized. Among these compounds, compound 16a exhibited good inhibitory activities toward PDE4B1 and PDE4D7 with mid‐nanomolar IC50 values and potential anti‐neuroinflammation activity in BV‐2 cells. Docking simulation of compound 16a in the PDE4 catalytic domain activity pocket revealed that compound 16a maybe assumed a “V‐shaped” conformation, extending the side chain to S‐pocket.

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Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis

Cited by 36 publications

References 65 publications

Inhibition of phosphodiesterase‐4 attenuates murine ulcerative colitis through interference with mucosal immunity

Inhibition of phosphodiesterase‐4 attenuates murine ulcerative colitis through interference with mucosal immunity

Pharmacodynamic assessment of apremilast for the treatment of moderate-to-severe plaque psoriasis

Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study

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