Reactome | PDE4A binds PDE4A inhibitors

PDE4A binds PDE4A inhibitors

Stable Identifier

R-HSA-9708275

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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The cAMP-specific PDE4A is highly expressed in cardiovascular tissues, smooth muscles, brain, keratinocytes and immune system cells, including T cells, monocytes, macrophages, neutrophils, dendritic cells and eosinophils. PDE4A inhibitors can effectively raise the intracellular level of cAMP, and help to modulate inflammatory and immune system responses. PDE4A inhibition represents an effective therapeutic strategy in many inflammatory conditions, including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, psoriasis, atopic dermatitis (AD), inflammatory bowel disease (IBD), rheumatic arthritis (RA), lupus and inflammation of the nervous system.

The prototypical PDE4 inhibitor is rolipram, originally developed as an antidepressant but was discontinued due to a very narrow therapeutic window. It continues to be used in research as a well-characterized PDE4 inhibitor (Huang & Mancini 2006). Approved PDE4A inhibitors are used to in the treatment of psoriasis and psoriatic arthritis (apremilast and crisaborole) (Kragstrup et al. 2019, Nazarian & Weinberg 2009, Hashim et al. 2020) or in inflammatory lung conditions such as asthma and COPD (ibudilast, roflumilast, piclamilast) (Rolan et al. 2009, Huang et al. 2006, Boswell-Smith & Spina 2007, Hatzelmann et al. 2010, Liu et al. 2018, Beeh et al. 2004, de Visser et al. 2008). Cilomilast and CHF-6001 are novel PDE4A inhibitors in trails for the treatment of COPD (Rennard et al. 2008, Liu et al. 2018, Singh et al. 2019, Phillips 2020).

Pentoxifylline is a xanthine derivative used as a drug to treat muscle pain in people with peripheral artery disease (Salhiyyah et al. 2015). Its antiviral, anti-inflammatory and brochodilatory effects highlight this drug as a therapeutic treatment alternative for patients with Covid-19 by helping reduce the production of the inflammatory cytokines without deleterious effects on the immune system to delay viral clearance (Maldonado et al. 2020, Henry et al. 2020, Ghasemnejad-Berenji et al. 2020, Dalamaga et al. 2020). Apremilast is being tested for its potential to reduce life-threatening immune hyperactivation that can manifest in some serious COVID-19 patients (Silva et al. 2020). PDE4 inhibition may attenuate the cytokine storm in Covid-19, through the upstream inhibition of pro-inflammatory molecules, particularly TNF-alpha (Dalamaga et al. 2020).

Literature References

PubMed ID	Title	Journal	Year
32540603	Repositioning of pentoxifylline as an immunomodulator and regulator of the renin-angiotensin system in the treatment of COVID-19 Maldonado, V, Loza-Mejía, MA, Chávez-Alderete, J	Med Hypotheses	2020
32715661	Hypothesis: Pentoxifylline is a potential cytokine modulator therapeutic in COVID-19 patients Hendry, BM, Stafford, N, Arnold, AD, Sangwaiya, A, Manglam, V, Rosen, SD, Arnold, J	Pharmacol Res Perspect	2020
15765929	Effects of piclamilast, a selective phosphodiesterase-4 inhibitor, on oxidative burst of sputum cells from mild asthmatics and stable COPD patients Beeh, KM, Beier, J, Lerch, C, Schulz, AK, Buhl, R	Lung	2004
20381629	The preclinical pharmacology of roflumilast--a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease Hatzelmann, A, Morcillo, EJ, Lungarella, G, Adnot, S, Sanjar, S, Beume, R, Schudt, C, Tenor, H	Pulm Pharmacol Ther	2010
32618402	COVID-19 patients with psoriasis and psoriatic arthritis on biologic immunosuppressant therapy vs apremilast in North Spain Queiro Silva, R, Armesto, S, González Vela, C, Naharro Fernández, C, González-Gay, MA	Dermatol Ther	2020
30833991	IL-12/IL-23p40 identified as a downstream target of apremilast in ex vivo models of arthritis Kragstrup, TW, Adams, M, Lomholt, S, Nielsen, MA, Heftdal, LD, Schäfer, P, Deleuran, B	Ther Adv Musculoskelet Dis	2019
33049737	Pentoxifylline, a drug with antiviral, anti-inflammatory and bronchodilatory effects may be a possible drug candidate for SARS-CoV-2 Ghasemnejad-Berenji, M, Pashapour, S, Sadeghpour, S	Med Princ Pract	2020
17168849	Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD Huang, Z, Mancini, JA	Curr Med Chem	2006
29602314	Use of cilomilast-loaded phosphatiosomes to suppress neutrophilic inflammation for attenuating acute lung injury: the effect of nanovesicular surface charge Liu, FC, Yu, HP, Lin, CY, Elzoghby, AO, Hwang, TL, Fang, JY	J Nanobiotechnology	2018
18044684	PDE4 inhibitors as potential therapeutic agents in the treatment of COPD-focus on roflumilast Boswell-Smith, V, Spina, D	Int J Chron Obstruct Pulmon Dis	2007
29443750	Effect and safety of roflumilast for chronic obstructive pulmonary disease in Chinese patients Liu, DY, Wang, ZG, Gao, Y, Zhang, HM, Zhang, YX, Wang, XJ, Peng, D	Medicine (Baltimore)	2018
26417854	Pentoxifylline for intermittent claudication Salhiyyah, K, Forster, R, Senanayake, E, Abdel-Hadi, M, Booth, A, Michaels, JA	Cochrane Database Syst Rev	2015
19929708	Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease Rolan, P, Hutchinson, M, Johnson, K	Expert Opin Pharmacother	2009
31399091	Effect of the inhaled PDE4 inhibitor CHF6001 on biomarkers of inflammation in COPD Singh, D, Beeh, KM, Colgan, B, Kornmann, O, Leaker, B, Watz, H, Lucci, G, Geraci, S, Emirova, A, Govoni, M, Nandeuil, MA	Respir Res	2019
32226383	Inhaled Phosphodiesterase 4 (PDE4) Inhibitors for Inflammatory Respiratory Diseases Phillips, JE	Front Pharmacol	2020
31279028	Crisaborole 2% ointment for the treatment of intertriginous, anogenital, and facial psoriasis: A double-blind, randomized, vehicle-controlled trial Hashim, PW, Chima, M, Kim, HJ, Bares, J, Yao, CJ, Singer, G, Chen, T, Genece, J, Baum, D, Kimmel, GW, Nia, JK, Gagliotti, M, Lebwohl, MG	J Am Acad Dermatol	2020
19105585	The efficacy and safety of cilomilast in COPD Rennard, S, Knobil, K, Rabe, KF, Morris, A, Schachter, N, Locantore, N, Canonica, WG, Zhu, Y, Barnhart, F	Drugs	2008
16313925	Preferential inhibition of human phosphodiesterase 4 by ibudilast Huang, Z, Liu, S, Zhang, L, Salem, M, Greig, GM, Chan, CC, Natsumeda, Y, Noguchi, K	Life Sci	2006
19876791	AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis Nazarian, R, Weinberg, JM	Curr Opin Investig Drugs	2009
32497535	Commentary: Phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19 Dalamaga, M, Karampela, I, Mantzoros, CS	Metabolism	2020