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phosphodiesterase 4A

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 1300

Nomenclature: phosphodiesterase 4A

Abbreviated Name: PDE4A

Family: Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs)

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 886 19p13.2 PDE4A phosphodiesterase 4A
Mouse - 844 9 7.73 cM Pde4a phosphodiesterase 4A, cAMP specific
Rat - 844 8q13 Pde4a phosphodiesterase 4A
Previous and Unofficial Names Click here for help
DPDE2 | phosphodiesterase E2 dunce homolog (Drosophila) | cAMP-specific 3',5'-cyclic phosphodiesterase 4A | dunce | phosphodiesterase 4A, cAMP-specific
Database Links Click here for help
Alphafold P27815 (Hs), O89084 (Mm), P54748 (Rn)
BRENDA 3.1.4.17
CATH/Gene3D 1.10.1300.10
ChEMBL Target CHEMBL254 (Hs), CHEMBL4964 (Rn)
DrugBank Target P27815 (Hs)
Ensembl Gene ENSG00000065989 (Hs), ENSMUSG00000032177 (Mm), ENSRNOG00000020828 (Rn)
Entrez Gene 5141 (Hs), 18577 (Mm), 25638 (Rn)
Human Protein Atlas ENSG00000065989 (Hs)
KEGG Enzyme 3.1.4.17
KEGG Gene hsa:5141 (Hs), mmu:18577 (Mm), rno:25638 (Rn)
OMIM 600126 (Hs)
Pharos P27815 (Hs)
SynPHARM 13762 (in complex with Ro20-1724)
UniProtKB P27815 (Hs), O89084 (Mm), P54748 (Rn)
Wikipedia PDE4A (Hs)
Enzyme Reaction Click here for help
EC Number: 3.1.4.17
Rank order of affinity (Human)
cyclic AMP >> cyclic GMP

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
piclamilast Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.8 pKi 2
⤷ pKi 8.8 (Ki 1.5x10-9 M) [2]
Description: Inhibition of rolipram binding to human PDE4
CDP840 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.0 pKi 12
⤷ pKi 8.0 (Ki 9.7x10-9 M) [12]
Description: Inhibition of [3H]-R-rolipram binding to recombinant human PDE-4 isoenzyme
rolipram Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.0 pIC50 16
⤷ pIC50 9.0 (IC50 1x10-9 M) [16]
MK-0359 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.8 pIC50 9
⤷ pIC50 8.8 (IC50 1.6x10-9 M) [9]
revamilast Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.6 pIC50 6
⤷ pIC50 8.6 (IC50 2.69x10-9 M) [6]
YM976 Small molecule or natural product Hs Inhibition 8.3 pIC50 1
⤷ pIC50 8.3 (IC50 5.01x10-9 M) [1]
MK-0873 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.2 pIC50 7
⤷ pIC50 8.2 (IC50 6x10-9 M) [7]
apremilast Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.8 pIC50 14
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [14]
Description: Potency against recombinant human PDE4A1A isoform in a TR-FRET assay.
ibudilast Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.3 pIC50 10
⤷ pIC50 7.3 (IC50 5.4x10-8 M) [10]
RS-25344 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.2 pIC50 13
⤷ pIC50 7.2 [13]
lenrispodun Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.8 pIC50 11
⤷ pIC50 6.8 (IC50 1.6x10-7 M) [11]
nerandomilast Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.6 pIC50 8
⤷ pIC50 6.6 (IC50 2.48x10-7 M) [8]
Description: Inhibition of PDE4A in vitro.
Ro20-1724 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.5 pIC50 16
⤷ pIC50 6.5 (IC50 3.16x10-7 M) [16]
ensifentrine Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.8 pIC50 3
⤷ pIC50 5.8 (IC50 1.479x10-6 M) [3]
Description: Inhibition of PDE4 obtained from human neutrophils
6-Hydroxy-5,7-dimethoxyflavone Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.1 pIC50 15
⤷ pIC50 5.1 (IC50 7.51x10-6 M) [15]
Description: Inhibition of PDE4A1A activity in vitro.
Inhibitor Comments
We have assigned the IC50 value for revamilast obtained from patent WO2006064355A2 to PDE4A, but the assay description in the patent document does not specify the isozyme tested, or the source of the PDE4 used [6].
Immunopharmacology Comments
PDE4 is a drug target, whose inhibition has anti-inflammatory action. PDE4 inhibitors have already entered clinical use, being employed in the treatment of inflammatory skin conditions such as psoriatic arthritis (apremilast) and atopic dermatitis (crisaborole).

COVID-19: The anti-inflammatory effect of PDE4 inhibition has been suggested as being a mechanism that could be applied to down-modulate the hyper-inflammation that can arise from SARS-CoV-2 infection [4-5].

References

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1. Aoki M, Kobayashi M, Ishikawa J, Saita Y, Terai Y, Takayama K, Miyata K, Yamada T. (2000) A novel phosphodiesterase type 4 inhibitor, YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one), with little emetogenic activity. J Pharmacol Exp Ther, 295 (1): 255-60. [PMID:10991987]

2. Ashton MJ, Cook DC, Fenton G, Karlsson JA, Palfreyman MN, Raeburn D, Ratcliffe AJ, Souness JE, Thurairatnam S, Vicker N. (1994) Selective type IV phosphodiesterase inhibitors as antiasthmatic agents. The syntheses and biological activities of 3-(cyclopentyloxy)-4-methoxybenzamides and analogues. J Med Chem, 37 (11): 1696-703. [PMID:8201604]

3. Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP. (2006) The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]. J Pharmacol Exp Ther, 318 (2): 840-8. [PMID:16682455]

4. Bridgewood C, Damiani G, Sharif K, Watad A, Bragazzi NL, Quartuccio L, Savic S, McGonagle D. (2020) Rationale for Evaluating PDE4 Inhibition for Mitigating against Severe Inflammation in COVID-19 Pneumonia and Beyond. Isr Med Assoc J, 22 (6): 335-339. [PMID:32558435]

5. Dalamaga M, Karampela I, Mantzoros CS. (2020) Commentary: Phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19. Metabolism, 109: 154282. [PMID:32497535]

6. Gharat LA, Gopalan B, Khairatkar-Joshi N. (2006) Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders. Patent number: WO2006064355A2. Assignee: Glenmark Pharmaceuticals S.A.. Priority date: 17/12/2004. Publication date: 22/06/2006.

7. Guay D, Boulet L, Friesen RW, Girard M, Hamel P, Huang Z, Laliberté F, Laliberté S, Mancini JA, Muise E et al.. (2008) Optimization and structure-activity relationship of a series of 1-phenyl-1,8-naphthyridin-4-one-3-carboxamides: identification of MK-0873, a potent and effective PDE4 inhibitor. Bioorg Med Chem Lett, 18 (20): 5554-8. [PMID:18835163]

8. Herrmann FE, Hesslinger C, Wollin L, Nickolaus P. (2022) BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral Treatment of Idiopathic Pulmonary Fibrosis. Front Pharmacol, 13: 838449. [PMID:35517783]

9. Huang Z, Dias R, Jones T, Liu S, Styhler A, Claveau D, Otu F, Ng K, Laliberte F, Zhang L et al.. (2007) L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition. Biochem Pharmacol, 73 (12): 1971-81. [PMID:17428447]

10. Kodimuthali A, Jabaris SS, Pal M. (2008) Recent advances on phosphodiesterase 4 inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. J Med Chem, 51 (18): 5471-89. [PMID:18686943]

11. Li P, Zheng H, Zhao J, Zhang L, Yao W, Zhu H, Beard JD, Ida K, Lane W, Snell G et al.. (2016) Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases. J Med Chem, 59 (3): 1149-64. [PMID:26789933]

12. Perry MJ, O'Connell J, Walker C, Crabbe T, Baldock D, Russell A, Lumb S, Huang Z, Howat D, Allen R et al.. (1998) CDP840: a novel inhibitor of PDE-4. Cell Biochem Biophys, 29: 113-32. [PMID:9631241]

13. Saldou N, Obernolte R, Huber A, Baecker PA, Wilhelm R, Alvarez R, Li B, Xia L, Callan O, Su C et al.. (1998) Comparison of recombinant human PDE4 isoforms: interaction with substrate and inhibitors. Cell Signal, 10 (6): 427-40. [PMID:9720765]

14. Schafer PH, Parton A, Capone L, Cedzik D, Brady H, Evans JF, Man HW, Muller GW, Stirling DI, Chopra R. (2014) Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal, 26 (9): 2016-29. [PMID:24882690]

15. Tsai YF, Chu TC, Chang WY, Wu YC, Chang FR, Yang SC, Wu TY, Hsu YM, Chen CY, Chang SH et al.. (2017) 6-Hydroxy-5,7-dimethoxy-flavone suppresses the neutrophil respiratory burst via selective PDE4 inhibition to ameliorate acute lung injury. Free Radic Biol Med, 106: 379-392. [PMID:28263828]

16. Wang P, Myers JG, Wu P, Cheewatrakoolpong B, Egan RW, Billah MM. (1997) Expression, purification, and characterization of human cAMP-specific phosphodiesterase (PDE4) subtypes A, B, C, and D. Biochem Biophys Res Commun, 234 (2): 320-4. [PMID:9177268]

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