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phosphodiesterase 4B

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Target id: 1301

Nomenclature: phosphodiesterase 4B

Abbreviated Name: PDE4B

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 - 736 1p31.3 PDE4B phosphodiesterase 4B
Mouse - 721 4 C6 Pde4b phosphodiesterase 4B, cAMP specific
Rat - 736 5q33 Pde4b phosphodiesterase 4B
Previous and Unofficial Names Click here for help
DPDE4 | phosphodiesterase E4 dunce homolog (Drosophila) | cAMP-specific 3',5'-cyclic phosphodiesterase 4B | Pde4B1 | Pde4B2 | Pde4B3 | Pde4B4 | phosphodiesterase 4B, cAMP-specific | phosphodiesterase 4B, cAMP specific
Database Links Click here for help
Alphafold Q07343 (Hs), P14646 (Rn)
BRENDA 3.1.4.17
CATH/Gene3D 1.10.1300.10
ChEMBL Target CHEMBL275 (Hs), CHEMBL3382 (Rn)
DrugBank Target Q07343 (Hs)
Ensembl Gene ENSG00000184588 (Hs), ENSMUSG00000028525 (Mm), ENSRNOG00000005905 (Rn)
Entrez Gene 5142 (Hs), 18578 (Mm), 24626 (Rn)
Human Protein Atlas ENSG00000184588 (Hs)
KEGG Enzyme 3.1.4.17
KEGG Gene hsa:5142 (Hs), mmu:18578 (Mm), rno:24626 (Rn)
OMIM 600127 (Hs)
Pharos Q07343 (Hs)
RefSeq Nucleotide NM_001037341 (Hs), NM_019840 (Mm), NM_017031 (Rn)
RefSeq Protein NP_001032418 (Hs), NP_062814 (Mm), NP_058727 (Rn)
SynPHARM 79214 (in complex with roflumilast)
13765 (in complex with rolipram)
UniProtKB Q07343 (Hs), P14646 (Rn)
Wikipedia PDE4B (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
CDP840 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.1 pKi 8
⤷ pKi 8.1 (Ki 8.5x10-9 M) [8]
Description: Inhibition of [3H]-R-rolipram binding to recombinant human PDE4B2 isoenzyme
roflumilast Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 9.4 pIC50 7
⤷ pIC50 9.4 [7]
MK-0359 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.3 pIC50 5
⤷ pIC50 9.3 (IC50 5x10-10 M) [5]
PF-07038124 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 9.3 pIC50 12
⤷ pIC50 9.3 (IC50 5x10-10 M) [12]
Description: Inhibition of PDE4B2 enzyme activity in a scintillation proximity assay
rolipram Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.0 pIC50 14
⤷ pIC50 9.0 (IC50 1x10-9 M) [14]
example 2 [WO2013026797A1] Small molecule or natural product Hs Inhibition 8.1 pIC50 9
⤷ pIC50 8.1 (IC50 7.2x10-9 M) [9]
nerandomilast Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 4
⤷ pIC50 8.0 (IC50 1x10-8 M) [4]
Description: Inhibition of PDE4B2 in vitro.
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 7.4 – 7.6 pIC50 11
⤷ pIC50 7.4 – 7.6 (IC50 4.3x10-8 – 2.7x10-8 M) [11]
Description: Potency against recombinant human PDE4B1 and B2 isoforms 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 7.2 pIC50 6
⤷ pIC50 7.2 (IC50 6.5x10-8 M) [6]
RS-25344 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.5 pIC50 10
⤷ pIC50 6.5 [10]
Ro20-1724 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.4 pIC50 14
⤷ pIC50 6.4 (IC50 3.98x10-7 M) [14]
CBS-3595 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.7 pIC50 2
⤷ pIC50 5.7 (IC50 1.9x10-6 M) [2]
Description: Determined against the PDE4B1 splice variant.
6-Hydroxy-5,7-dimethoxyflavone Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.1 pIC50 13
⤷ pIC50 5.1 (IC50 8.58x10-6 M) [13]
Description: Inhibition of PDE4B2 activity in vitro.
crisaborole Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition - - 1
⤷ [1]
roflupram Small molecule or natural product Immunopharmacology Ligand N/A Inhibition - - 16
⤷ Knocking down the expression of PDE4B in primary microglial cells led to enhanced level of LC-3 II and decreased activation of inflammasome. [16]
View species-specific inhibitor tables
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). PDE4B is the predominant phosphodiesterase subtype in monocytes and neutrophils and this is thought to be the sub-type central to inflammatory action of phosphodiesterases [15]. The development compound difamilast is reported to show selectivity for this PDE4 isoform [3].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
General Comments
PDE4B is the predominant phosphodiesterase subtype in monocytes and neutrophils and this is thought to be the sub-type central to inflammatory action of phosphodiesterases [15].

References

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1. Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V, Freund Y, Kimura R, Maples KR, Plattner JJ. (2009) Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett, 19 (8): 2129-32. [PMID:19303290]

2. Albrecht W, Unger A, Bauer SM, Laufer SA. (2017) Discovery of N-{4-[5-(4-Fluorophenyl)-3-methyl-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-acetamide (CBS-3595), a Dual p38α MAPK/PDE-4 Inhibitor with Activity against TNFα-Related Diseases. J Med Chem, 60 (13): 5290-5305. [PMID:28613871]

3. Hanifin JM, Ellis CN, Frieden IJ, Fölster-Holst R, Stein Gold LF, Secci A, Smith AJ, Zhao C, Kornyeyeva E, Eichenfield LF. (2016) OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): A phase-II randomized, double-blind, placebo-controlled study. J Am Acad Dermatol, 75 (2): 297-305. [PMID:27189825]

4. 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]

5. 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]

6. 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]

7. Lunniss CJ, Cooper AW, Eldred CD, Kranz M, Lindvall M, Lucas FS, Neu M, Preston AG, Ranshaw LE, Redgrave AJ et al.. (2009) Quinolines as a novel structural class of potent and selective PDE4 inhibitors: optimisation for oral administration. Bioorg Med Chem Lett, 19 (5): 1380-5. [PMID:19195882]

8. 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]

9. Pouzet PAJ, Nickoluas P, Werthmann U, Frutos RP, Yang BS, Kim S, Mulder JA, Patel N, Senanayake CH, Tampone TG et al.. (2013) Novel piperidino-dihydrothienopyrimidine sulfoxides and their use for treating copd and asthma. Patent number: WO2013026797A1. Assignee: Boehringer Ingelheim International Gmbh. Priority date: 24/08/2011. Publication date: 28/02/2013.

10. 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]

11. 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]

12. Strohbach JW, Akama T, Blakemore DC, Jacobs RT, Jones P, Limburg DC, Oderinde MS, Perry MA, Plattner JJ, Torella RF et al.. (2020) Boron Containing PDE4 Inhibitors. Patent number: US20200108083A1. Assignee: Pfizer Inc.. Priority date: 05/10/2018. Publication date: 09/04/2020.

13. 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]

14. 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]

15. Wang P, Wu P, Ohleth KM, Egan RW, Billah MM. (1999) Phosphodiesterase 4B2 is the predominant phosphodiesterase species and undergoes differential regulation of gene expression in human monocytes and neutrophils. Mol Pharmacol, 56 (1): 170-4. [PMID:10385698]

16. You T, Cheng Y, Zhong J, Bi B, Zeng B, Zheng W, Wang H, Xu J. (2017) Roflupram, a Phosphodiesterase 4 Inhibitior, Suppresses Inflammasome Activation through Autophagy in Microglial Cells. ACS Chem Neurosci, 8 (11): 2381-2392. [PMID:28605578]

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