PDE4B

Summary

PDE4B (phosphodiesterase 4B, HGNC:8781) is a protein-coding gene on chromosome 1p31.3, encoding 3’,5’-cyclic-AMP phosphodiesterase 4B (Q07343). Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

This gene is a member of the type IV, cyclic AMP (cAMP)-specific, cyclic nucleotide phosphodiesterase (PDE) family. The encoded protein regulates the cellular concentrations of cyclic nucleotides and thereby play a role in signal transduction. Altered activity of this protein has been associated with schizophrenia and bipolar affective disorder. Alternative splicing and the use of alternative promoters results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 5142 — RefSeq curated summary.

At a glance

• GWAS associations: 43
• Clinical variants (ClinVar): 59 total
• Druggable target: yes — 55 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002600

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8781
Approved symbol	PDE4B
Name	phosphodiesterase 4B
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000184588
Ensembl biotype	protein_coding
OMIM	600127
Entrez	5142

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 10 protein_coding, 6 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000329654, ENST00000341517, ENST00000371045, ENST00000371048, ENST00000412480, ENST00000423207, ENST00000480109, ENST00000483863, ENST00000490695, ENST00000491340, ENST00000524999, ENST00000526197, ENST00000526666, ENST00000528771, ENST00000531025, ENST00000531358, ENST00000532040, ENST00000534463

RefSeq mRNA: 7 — MANE Select: NM_002600 NM_001037339, NM_001037340, NM_001037341, NM_001297440, NM_001297441, NM_001297442, NM_002600

CCDS: CCDS30742, CCDS30743, CCDS632, CCDS72802

Canonical transcript exons

ENST00000341517 — 17 exons

Exon	Start	End
ENSE00001294554	66365667	66365766
ENSE00001295605	66247460	66247654
ENSE00001304431	66367943	66368065
ENSE00001311355	66363407	66363571
ENSE00001314677	65918597	65918835
ENSE00001321190	66355527	66355620
ENSE00001326709	66367696	66367850
ENSE00001454221	65913245	65913356
ENSE00001597852	66368787	66368969
ENSE00001777645	65792895	65793248
ENSE00002180148	66372313	66374574
ENSE00003531813	66257793	66257863
ENSE00003566634	66332508	66332620
ENSE00003614636	66257647	66257683
ENSE00003669256	66363168	66363266
ENSE00003670692	66361615	66361793
ENSE00003687104	66266038	66266087

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 98.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 56.2948 / max 7896.5088, expressed in 1315 samples.

FANTOM5 promoters (27 alternative TSS)

Promoter ID	TPM avg	Samples expressed
3335	14.3068	950
3332	11.5558	648
3337	8.4449	840
3331	6.6059	517
3334	4.6378	512
3316	3.8169	161
3333	1.5186	256
3312	1.0798	124
3314	0.6911	112
3338	0.6872	313

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	98.78	gold quality
cartilage tissue	UBERON:0002418	98.06	gold quality
subthalamic nucleus	UBERON:0001906	96.84	gold quality
inferior vagus X ganglion	UBERON:0005363	96.77	gold quality
superior vestibular nucleus	UBERON:0007227	96.75	gold quality
ventral tegmental area	UBERON:0002691	96.49	gold quality
medulla oblongata	UBERON:0001896	96.29	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.91	gold quality
lateral globus pallidus	UBERON:0002476	95.91	gold quality
middle temporal gyrus	UBERON:0002771	95.71	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.56	gold quality
pons	UBERON:0000988	95.26	gold quality
substantia nigra pars compacta	UBERON:0001965	94.87	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.58	gold quality
entorhinal cortex	UBERON:0002728	94.24	gold quality
spinal cord	UBERON:0002240	94.09	gold quality
globus pallidus	UBERON:0001875	94.01	gold quality
occipital lobe	UBERON:0002021	93.81	gold quality
bone marrow cell	CL:0002092	93.80	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.73	gold quality
postcentral gyrus	UBERON:0002581	93.68	gold quality
CA1 field of hippocampus	UBERON:0003881	93.68	gold quality
inferior olivary complex	UBERON:0002127	93.66	gold quality
parietal lobe	UBERON:0001872	93.58	gold quality
middle frontal gyrus	UBERON:0002702	93.58	gold quality
deltoid	UBERON:0001476	93.53	gold quality
primary visual cortex	UBERON:0002436	93.41	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.37	gold quality
midbrain	UBERON:0001891	93.35	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.34	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	4888.62
E-HCAD-30	yes	4663.39
E-MTAB-10885	yes	502.17
E-MTAB-9841	yes	428.00
E-HCAD-25	yes	68.52
E-GEOD-135922	yes	28.22
E-GEOD-93593	yes	4.86
E-CURD-89	no	908.88
E-GEOD-36552	no	36.97
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, GLI1, IRF6, ZNF804A

miRNA regulators (miRDB)

108 targeting PDE4B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-7845-5P	99.88	64.88	771

Literature-anchored findings (GeneRIF, showing 40)

• Inhibition of PDE3B augments PDE4 inhibitor-induced apoptosis in a subset of patients with chronic lymphocytic leukemia (PMID:11839681)
• TCR-dependent signaling activates PDE4B2 and enhances interleukin-2 production in T cells. (PMID:14585965)
• clinically relevant PDE4 and PI3K/AKT inhibitors might be useful in the treatment of Diffuse large B-cell lymphoma and additional B-lymphoid malignancies with increased PDE4B expression (PMID:15331441)
• a mechanistic model whereby DISC1 sequesters phosphodiesterase 4B in resting cells and releases it in an activated state in response to elevated cAMP (PMID:16293762)
• Reverse-transcription polymerase chain reaction confirmed increased expression of GADD45A, BTG2, PDE4B, and CEBPD and downregulation of TOB1 in skeletal muscle intradialysis. (PMID:16997058)
• Compartmentalized PDE4B acts as a sink to drain cAMP from discrete locations, resulting in multiple domains with different cAMP concentrations. (PMID:17088426)
• PDE4B haplotype alters the genetic risk of schizophrenia in the Scottish population complements the known participation of this gene in biological processes associated with mental illness (PMID:17417055)
• Behavioral phenotypes of Disc1 missense mutations in mice and consequences for PDE4B (PMID:17481393)
• A super-short, brain specific isoform of human PDE4B, PDE4B5, was identified. It has cAMP hydrolyzing activity and is inhibited by PDE4 inhibitors. PDE4B5 bind to DISC1. The 16 N-terminal residues are identical to the corresponding residues of PDE4D6. (PMID:17519386)
• Altered DISC1-PDE4B interaction may thus underlie the symptoms of some cases of schizophrenia and depression.(Review) (PMID:17823207)
• Our result suggests that variations at the PDE4B locus may play a significant role in the etiology of SZ in the Japanese population. (PMID:18329668)
• the present observations suggest that dysregulation of intracellular signaling mediated by PDE4B is a significant factor in the cause and expression, respectively, of schizophrenia. (PMID:18394866)
• the PDE4B gene itself does not link to major depressive disorder (MDD) but the elevated mRNA levels of PDE4B might be implicated in the pathophysiology of MDD. (PMID:18785206)
• NDE1, NDEL1 and LIS1, together with their binding partner dynein, associate with DISC1, PDE4B and PDE4D within the cell, and provide evidence that this complex is present at the centrosome. (PMID:18983980)
• There was no strong evidence for association with PDE4B in schizophrenia. (PMID:19632097)
• phosphodiesterase 4B2 gene is an effector of Toll-like receptor signaling in astrocytes, and that its up-regulation at the protein level is controlled by complex mechanisms (PMID:19728060)
• results do not support a genetic association between tardive dyskinesia and PDE4B (PMID:20436352)
• found a significant association between PDE4B and PD in the haplotype analysis. Sex-specific analyses demonstrated that PDE4B was associated with PD in females. results suggest PDE4B may play a role in the pathophysiology of PD in the Japanese population. (PMID:21184794)
• these data allow the assignment of different PDE4 subtypes to distinct functions of human lung fibroblasts and highlight the predominant role of PDE4B in controlling pathophysiological processes of human lung fibroblasts. (PMID:21520048)
• Molecular dynamic simulations (with data from crystal structure of catalytic domain of PDE4B with cAMP bound) are used to investigate the catalytic mechanism of PDE4B in the hydrolysis of cAMP. (PMID:21595828)
• Overexpression of the PDE4B in diffuse large B-cell lymphoma (DLBCL) impinge on the same genes/pathways that are abnormally active in GC-resistant tumors. (PMID:21742807)
• The reported anti-inflammatory activity of bresol might be attributed to its abilities to inhibit PDE4B and thus elevate cAMP levels in human monocytes. (PMID:21854221)
• a study of Northwestern Han Chinese found that rs472952 is significantly associated with schizophrenia (SCZ) and rs7537440 is associated with SCZ in females; results provide further evidence that PDE4B may play important roles in the etiology of SCZ (PMID:22160351)
• PDE4B was downregulated and the protein kinase A pathway was activated in castration-resistant LNCaP prostate cancer cells. PDE4B expression was reduced in advanced prostate cancer and PDE4B knockdown promoted castration-resistant growth of LNCaP cells. (PMID:22529021)
• PDE4B mediates ERK-dependent up-regulation of mucin MUC5AC by S. pneumoniae by inhibiting cAMP-PKA-dependent MKP-1 pathway. (PMID:22610099)
• Short Disrupted-in-Schizophrenia (DISC)1 splice variants show reduced or no binding to nudE nuclear distribution E homolog (NDEL)1 and PDE4B proteins but fully interact with fasciculation/elongation zeta (FEZ)1 and glycogen synthase kinase 3 GSK3beta. (PMID:22832604)
• PDE4B was found to be highly expressed in CD4+ lymphoid cancer cells, which suggests that it may represent a physiological role unique to the CD8+ and lymphoid cancer cells and thus might represent a target for treatment of certain lymphoid diseases (PMID:23451206)
• ototopical post-inoculation administration of a PDE4 inhibitor suppresses inflammation in this animal model, thus demonstrating the therapeutic potential of targeting PDE4 (PMID:23575688)
• PDE4B gene may be involved in the testicular abnormalities of men with DS and cryptorchidism. (PMID:25546171)
• analysis of the mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cbeta and p65 (PMID:25831493)
• Our results support previously reported association of PDE4B variations with schizophrenia in other populations. (PMID:25926551)
• Our results suggest that PDE4B does not play an important role during the chemotactic response of human neutrophils (PMID:26011935)
• This meta-analysis suggests that PDE4B SNPs are genetically associated with susceptibility to schizophrenia. (PMID:26756575)
• HTT forms a ternary protein complex with the scaffolding protein DISC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. (PMID:28263187)
• Low PDE4B expression is associated with sepsis. (PMID:28356347)
• Smurf2, an E3 ubiquitin ligase, interacts with PDE4B and attenuates liver fibrosis through miR-132 mediated CTGF inhibition. (PMID:29100790)
• Data suggest that maternal glycemic response during pregnancy is associated with lower DNA methylation of 4 CpG sites within PDE4B gene in placenta (collected after term birth); 3 additional CpG sites are differentially methylated relative to maternal glucose response within TNFRSF1B, LDLR, and BLM genes. (TNFRSF1B = TNF receptor superfamily member-1B; LDLR = low density lipoprotein receptor; BLM = Bloom syndrome protein) (PMID:29752424)
• in psoriatic arthritis, dysregulated miR-23a expression contributes to synovial inflammation through enhanced synovial fibroblasts activation, via PDE4B signalling (PMID:30181004)
• Study combined mutational analysis in the Apc mutated mice with published studies of frank colon cancer in patients to deduce that Pde4b has two strong biological functions. It negatively regulates colonic adenomagenesis in Apc mutated mice. In patients, PDE4B is most commonly inactivated by an epigenetic process. (PMID:30188895)
• PDE4B gene may play a role in the pathogenesis of OLP. (PMID:30229893)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pde4ba	ENSDARG00000032868
danio_rerio	pde4bb	ENSDARG00000074233
mus_musculus	Pde4b	ENSMUSG00000028525
rattus_norvegicus	Pde4b	ENSRNOG00000005905
drosophila_melanogaster	dnc	FBGN0000479
caenorhabditis_elegans		WBGENE00020114

Paralogs (20): PDE4A (ENSG00000065989), PDE8A (ENSG00000073417), PDE6C (ENSG00000095464), PDE4C (ENSG00000105650), PDE10A (ENSG00000112541), PDE8B (ENSG00000113231), PDE4D (ENSG00000113448), PDE1A (ENSG00000115252), PDE1B (ENSG00000123360), PDE11A (ENSG00000128655), PDE6A (ENSG00000132915), PDE6B (ENSG00000133256), PDE5A (ENSG00000138735), PDE3B (ENSG00000152270), PDE1C (ENSG00000154678), PDE9A (ENSG00000160191), PDE7B (ENSG00000171408), PDE3A (ENSG00000172572), PDE2A (ENSG00000186642), PDE7A (ENSG00000205268)

Protein

Protein identifiers

3’,5’-cyclic-AMP phosphodiesterase 4B — Q07343 (reviewed: Q07343)

Alternative names: DPDE4, PDE32, cAMP-specific phosphodiesterase 4B

All UniProt accessions (7): Q07343, E9PJ03, E9PMG3, E9PNB0, E9PR34, H0YCV7, X5DNX5

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.

Subunit / interactions. Interacts with DISC1.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in brain, heart, lung and skeletal muscle. Expressed in white blood cells. Brain-specific isoform.

Activity regulation. Inhibited by rolipram.

Cofactor. Binds 2 divalent metal cations per subunit. Site 1 may preferentially bind zinc ions. Binds 2 divalent metal cations per subunit. Site 2 has a preference for magnesium and/or manganese ions.

Pathway. Purine metabolism; 3’,5’-cyclic AMP degradation; AMP from 3’,5’-cyclic AMP: step 1/1.

Similarity. Belongs to the cyclic nucleotide phosphodiesterase family. PDE4 subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q07343-1	PDE4B1	yes
Q07343-2	PDE4B2
Q07343-3	PDE4B3
Q07343-4	PDE4B5

RefSeq proteins (7): NP_001032416, NP_001032417, NP_001032418, NP_001284369, NP_001284370, NP_001284371, NP_002591* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002073	PDEase_catalytic_dom	Domain
IPR003607	HD/PDEase_dom	Domain
IPR023088	PDEase	Family
IPR023174	PDEase_CS	Conserved_site
IPR036971	PDEase_catalytic_dom_sf	Homologous_superfamily
IPR040844	PDE4_UCR	Domain

Pfam: PF00233, PF18100

Enzyme classification (BRENDA):

• EC 3.1.4.53 — 3’,5’-cyclic-AMP phosphodiesterase (BRENDA: 28 organisms, 62 substrates, 307 inhibitors, 60 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ADENOSINE 3’,5’-CYCLIC PHOSPHATE	—	34
3’,5’-CAMP	0.0003–0.5	13
CAMP	0.0001–0.191	9
CGMP	0.24–0.427	2
3’,5’-CGMP	1.6	1
GUANOSINE 3’,5’-CYCLIC PHOSPHATE	0.124	1

Catalyzed reactions (Rhea), 1 shown:

• 3’,5’-cyclic AMP + H2O = AMP + H(+) (RHEA:25277)

UniProt features (78 total): helix 29, binding site 16, turn 9, strand 5, region of interest 4, splice variant 4, mutagenesis site 4, modified residue 3, chain 1, domain 1, sequence variant 1, active site 1

Structure

Experimental structures (PDB)

43 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4KP6	X-RAY DIFFRACTION	1.5
2CHM	X-RAY DIFFRACTION	1.6
5OHJ	X-RAY DIFFRACTION	1.6
3FRG	X-RAY DIFFRACTION	1.7
6BOJ	X-RAY DIFFRACTION	1.7
3D3P	X-RAY DIFFRACTION	1.75
3GWT	X-RAY DIFFRACTION	1.75
1F0J	X-RAY DIFFRACTION	1.77
3HC8	X-RAY DIFFRACTION	1.79
3HDZ	X-RAY DIFFRACTION	1.8
5K6J	X-RAY DIFFRACTION	1.86
8OEG	X-RAY DIFFRACTION	1.89
4MYQ	X-RAY DIFFRACTION	1.9
1XM6	X-RAY DIFFRACTION	1.92
2QYL	X-RAY DIFFRACTION	1.95
3O0J	X-RAY DIFFRACTION	1.95
1RO6	X-RAY DIFFRACTION	2
1ROR	X-RAY DIFFRACTION	2
3O57	X-RAY DIFFRACTION	2
1XLZ	X-RAY DIFFRACTION	2.06
1RO9	X-RAY DIFFRACTION	2.13
1TB5	X-RAY DIFFRACTION	2.15
4NW7	X-RAY DIFFRACTION	2.15
1XLX	X-RAY DIFFRACTION	2.19
3HMV	X-RAY DIFFRACTION	2.23
1XOS	X-RAY DIFFRACTION	2.28
1XMU	X-RAY DIFFRACTION	2.3
3W5E	X-RAY DIFFRACTION	2.3
1XM4	X-RAY DIFFRACTION	2.31
1XN0	X-RAY DIFFRACTION	2.31

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q07343-F1	71.22	0.48

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 406 (proton donor)

Ligand- & substrate-binding residues (16): 410; 446; 447; 447; 447; 447; 447; 564; 564; 615; 615; 618 …

Post-translational modifications (3): 290, 659, 661

Mutagenesis-validated functional residues (4):

Position	Phenotype
567–575	increases substrate selectivity for cgmp.
567	changes substrate selectivity from camp-specific to dual camp and cgmp binding and hydrolysis; when associated with q-57
575	changes substrate selectivity from camp-specific to dual camp and cgmp binding and hydrolysis; when associated with a-56
652	changes substrate selectivity from camp-specific to dual camp and cgmp binding and hydrolysis; when associated with a-56

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-180024	DARPP-32 events

MSigDB gene sets: 584 (showing top): VALK_AML_WITH_FLT3_ITD, GSE45365_NK_CELL_VS_CD11B_DC_DN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, MODULE_52, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, MODULE_45, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_DN, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS

GO Biological Process (16): neutrophil homeostasis (GO:0001780), cAMP catabolic process (GO:0006198), neutrophil chemotaxis (GO:0030593), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-2 production (GO:0032743), T cell receptor signaling pathway (GO:0050852), leukocyte migration (GO:0050900), cellular response to lipopolysaccharide (GO:0071222), cellular response to xenobiotic stimulus (GO:0071466), cellular response to epinephrine stimulus (GO:0071872), negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway (GO:0071878), regulation of cardiac muscle cell contraction (GO:0086004), negative regulation of cAMP/PKA signal transduction (GO:0141162), negative regulation of relaxation of cardiac muscle (GO:1901898), regulation of calcium ion transmembrane transport via high voltage-gated calcium channel (GO:1902514), signal transduction (GO:0007165)

GO Molecular Function (11): 3’,5’-cyclic-AMP phosphodiesterase activity (GO:0004115), calcium channel regulator activity (GO:0005246), cAMP binding (GO:0030552), gamma-tubulin binding (GO:0043015), transmembrane transporter binding (GO:0044325), metal ion binding (GO:0046872), 3’,5’-cyclic-GMP phosphodiesterase activity (GO:0047555), 3’,5’-cyclic-nucleotide phosphodiesterase activity (GO:0004114), protein binding (GO:0005515), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787)

GO Cellular Component (13): gamma-tubulin complex (GO:0000930), centrosome (GO:0005813), cytosol (GO:0005829), voltage-gated calcium channel complex (GO:0005891), synaptic vesicle (GO:0008021), postsynaptic density (GO:0014069), Z disc (GO:0030018), dendritic spine (GO:0043197), excitatory synapse (GO:0060076), cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Opioid Signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
positive regulation of cytokine production	2
cellular response to chemical stimulus	2
3’,5’-cyclic-nucleotide phosphodiesterase activity	2
microtubule organizing center	2
leukocyte homeostasis	1
myeloid cell homeostasis	1
purine ribonucleotide catabolic process	1
cyclic nucleotide catabolic process	1
cAMP metabolic process	1
granulocyte chemotaxis	1
neutrophil migration	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
antigen receptor-mediated signaling pathway	1
immune system process	1
cell migration	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
response to xenobiotic stimulus	1
response to epinephrine	1
adenylate cyclase-activating adrenergic receptor signaling pathway	1
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
regulation of cardiac muscle contraction	1
cardiac muscle cell contraction	1
regulation of actin filament-based movement	1
cAMP/PKA signal transduction	1
regulation of cAMP/PKA signal transduction	1
negative regulation of intracellular signal transduction	1
relaxation of cardiac muscle	1
negative regulation of relaxation of muscle	1
regulation of relaxation of cardiac muscle	1
calcium ion transmembrane transport via high voltage-gated calcium channel	1
regulation of calcium ion transmembrane transport	1
cell communication	1
cellular process	1

Protein interactions and networks

STRING

1396 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDE4B	DISC1	Q9NRI5	998
PDE4B	ALDH7A1	P49419	942
PDE4B	NDE1	Q9NXR1	802
PDE4B	NDEL1	Q9GZM8	801
PDE4B	SLC25A19	Q9HC21	730
PDE4B	IFT54	Q8TDR0	723
PDE4B	ATF5	Q9Y2D1	675
PDE4B	RAPGEF3	O95398	668
PDE4B	AKAP1	Q92667	657
PDE4B	AKAP7	O43687	638
PDE4B	GSK3B	P49841	634
PDE4B	ADCY8	P40145	605
PDE4B	PIK3CG	P48736	601
PDE4B	RAPGEF4	Q8WZA2	572
PDE4B	ADCY3	O60266	558

IntAct

15 interactions, top by confidence:

A	B	Type	Score
PDE4B	CACNA1C	psi-mi:“MI:0915”(physical association)	0.500
PDE4D	PDE4B	psi-mi:“MI:0915”(physical association)	0.500
PDE4B	MAGEA11	psi-mi:“MI:0915”(physical association)	0.370
PDE4B	RCBTB2	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
APOA1	CNMD	psi-mi:“MI:0914”(association)	0.350
ALB	CDC45	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
NPAS1	CIBAR1	psi-mi:“MI:0914”(association)	0.350
DISC1	NME2P1	psi-mi:“MI:0914”(association)	0.350
PDE4D	OXSR1	psi-mi:“MI:0914”(association)	0.350
VCP	FAM171A2	psi-mi:“MI:0914”(association)	0.350
PDE4B	DISC1	psi-mi:“MI:0915”(physical association)	0.000
DISC1	PDE4B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (75): PDE4B (Affinity Capture-RNA), PDE4B (Affinity Capture-RNA), PDE4B (Affinity Capture-MS), PDE4B (Affinity Capture-MS), PDE4B (Affinity Capture-MS), PDE4B (Affinity Capture-Western), SMURF2 (Affinity Capture-Western), PDE4B (Reconstituted Complex), PDE4B (Affinity Capture-MS), PDE4B (Affinity Capture-MS), PDE4B (Affinity Capture-MS), FUS (Protein-RNA), PDE4B (Affinity Capture-RNA), P4HB (Protein-RNA), RIC8A (Protein-RNA)

ESM2 similar proteins: A8WRV1, B0XUR7, B4GXC2, B4IMC3, B4NSS9, B5DK35, G5EFI8, O15075, O60333, O62305, O88658, P14270, P14646, P26570, P30645, P32945, P33329, P34350, P48459, P48460, P78968, Q01063, Q05999, Q07343, Q08499, Q21017, Q22000, Q22712, Q39183, Q4WM22, Q5R686, Q5RDX4, Q5U243, Q60575, Q66HD5, Q6GPD0, Q6NRL1, Q6P158, Q6P5D3, Q7PLI7

Diamond homologs: A0A077YBL0, B7YZV4, O18696, O60658, O88502, O89084, O95263, P06776, P12252, P14100, P14270, P14644, P14646, P27815, P30645, P54748, P54750, Q01061, Q01063, Q01064, Q01065, Q01066, Q07343, Q08493, Q08499, Q14123, Q3UEI1, Q61481, Q63421, Q64338, Q64395, Q6NNF2, Q86H13, Q8I5V4, Q8IRU4, Q9I7S6, Q9N2V9, Q9W4S9, Q9W4T4, B3LVW5

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
GSK256066	down-regulates	PDE4B	“chemical inhibition”
PRKACA	“up-regulates activity”	PDE4B	phosphorylation
PKA	“up-regulates activity”	PDE4B	phosphorylation
MAPK1	“up-regulates activity”	PDE4B	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

59 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	1
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

4286 predictions. Top by Δscore:

Variant	Effect	Δscore
1:66112883:G:GG	donor_gain	1.0000
1:66257642:A:AG	acceptor_gain	1.0000
1:66257645:A:AG	acceptor_gain	1.0000
1:66257646:G:GG	acceptor_gain	1.0000
1:66257789:CTA:C	acceptor_loss	1.0000
1:66257790:TAGGT:T	acceptor_loss	1.0000
1:66257791:A:AG	acceptor_gain	1.0000
1:66257791:A:C	acceptor_loss	1.0000
1:66257792:G:A	acceptor_loss	1.0000
1:66257792:G:GG	acceptor_gain	1.0000
1:66257864:G:GG	donor_gain	1.0000
1:66257865:TAA:T	donor_loss	1.0000
1:66332506:A:AG	acceptor_gain	1.0000
1:66332507:G:GG	acceptor_gain	1.0000
1:66332507:GAA:G	acceptor_gain	1.0000
1:66332619:AGG:A	donor_loss	1.0000
1:66332620:GGTAA:G	donor_loss	1.0000
1:66332621:GT:G	donor_loss	1.0000
1:66332622:T:G	donor_loss	1.0000
1:66355525:A:AG	acceptor_gain	1.0000
1:66355526:G:GG	acceptor_gain	1.0000
1:66361603:T:TA	acceptor_gain	1.0000
1:66361607:T:A	acceptor_gain	1.0000
1:66361610:T:A	acceptor_gain	1.0000
1:66361610:TGCA:T	acceptor_loss	1.0000
1:66361611:GCA:G	acceptor_loss	1.0000
1:66361612:CA:C	acceptor_loss	1.0000
1:66361613:A:AG	acceptor_gain	1.0000
1:66361613:AGA:A	acceptor_loss	1.0000
1:66361614:G:GT	acceptor_gain	1.0000

AlphaMissense

4928 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:66247578:T:C	F134L	1.000
1:66247580:T:A	F134L	1.000
1:66247580:T:G	F134L	1.000
1:66257797:T:C	L173P	1.000
1:66332555:T:A	W228R	1.000
1:66332555:T:C	W228R	1.000
1:66332558:T:C	C229R	1.000
1:66332560:T:G	C229W	1.000
1:66332571:T:C	L233P	1.000
1:66332598:T:A	V242D	1.000
1:66332610:C:A	A246D	1.000
1:66355527:T:C	F250L	1.000
1:66355528:T:C	F250S	1.000
1:66355528:T:G	F250C	1.000
1:66355529:C:A	F250L	1.000
1:66355529:C:G	F250L	1.000
1:66355540:T:A	L254Q	1.000
1:66355540:T:C	L254P	1.000
1:66355546:G:C	R256P	1.000
1:66355552:T:C	L258P	1.000
1:66355603:T:A	I275N	1.000
1:66355603:T:G	I275S	1.000
1:66363189:T:A	W348R	1.000
1:66363189:T:C	W348R	1.000
1:66363503:C:G	H406D	1.000
1:66365674:T:C	F431S	1.000
1:66365718:C:G	H446D	1.000
1:66365721:G:C	D447H	1.000
1:66365722:A:C	D447A	1.000
1:66365722:A:G	D447G	1.000

dbSNP variants (sampled 300 via entrez): RS1000000378 (1:65873721 T>C,G), RS1000001548 (1:65963264 C>A,T), RS1000012620 (1:65820708 C>G,T), RS1000012782 (1:66094265 C>T), RS1000014008 (1:66015294 C>G), RS1000014427 (1:66250252 C>G), RS1000016514 (1:65881613 T>C), RS1000026012 (1:66180836 A>C), RS1000050879 (1:66117672 G>A), RS1000055498 (1:66120830 G>A), RS1000058082 (1:66255698 G>A,C,T), RS1000059255 (1:66168430 G>A), RS1000059667 (1:66237586 G>A,T), RS1000063921 (1:66298549 C>G), RS1000068258 (1:65821898 AG>A)

Disease associations

OMIM: gene MIM:600127 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

43 associations (top):

Study	Trait	p-value
GCST000110_5	Echocardiographic traits	7.000000e-06
GCST001320_9	Acute lymphoblastic leukemia (childhood)	6.000000e-06
GCST001514_4	Economic and political preferences (feminism/equality)	2.000000e-06
GCST001693_10	Acute lymphoblastic leukemia (childhood)	9.000000e-06
GCST001693_6	Acute lymphoblastic leukemia (childhood)	5.000000e-06
GCST002440_1	Staphylococcus aureus infection	7.000000e-07
GCST003994_11	Age at voice drop	1.000000e-10
GCST004121_9	Fibrinogen levels	5.000000e-12
GCST004122_31	Fibrinogen levels	5.000000e-11
GCST005171_27	QT interval	2.000000e-06
GCST005790_78	Rosacea symptom severity	6.000000e-06
GCST005897_32	Low tan response	2.000000e-14
GCST007201_389	Schizophrenia	1.000000e-07
GCST007201_49	Schizophrenia	1.000000e-07
GCST007323_94	Risk-taking tendency (4-domain principal component model)	1.000000e-09
GCST007327_220	Smoking status (ever vs never smokers)	2.000000e-13
GCST007559_17	Sleep duration (short sleep)	5.000000e-09
GCST007576_66	Chronotype	5.000000e-09
GCST007603_24	Smoking initiation	1.000000e-09
GCST008362_137	Birth weight	1.000000e-08
GCST008559_3	Anxiety and stress-related disorders	5.000000e-11
GCST008561_1	Anxiety and stress-related disorders (psychiatric co-morbidity covariate model)	2.000000e-08
GCST008562_1	Anxiety and stress-related disorders (psychiatric co-morbidity weighting design)	1.000000e-11
GCST008563_1	Anxiety and stress-related disorders (including obsessive-compulsive disorder)	1.000000e-10
GCST008564_1	Anxiety and stress-related disorders (excluding co-morbid schizophrenia)	4.000000e-10
GCST008565_1	Anxiety and stress-related disorders (excluding adjustment disorder)	2.000000e-11
GCST008566_1	Anxiety disorders	3.000000e-07
GCST008567_1	Stress-related disorders	6.000000e-09
GCST008755_2	Phenylephrine infusion rate during anesthesia	4.000000e-07
GCST008757_18	Alcohol consumption	3.000000e-12

EFO canonical traits (19, from GWAS)

EFO ID	Trait name
EFO:0004294	left atrial function
EFO:0004298	cardiovascular measurement
EFO:0004827	economic and social preference
EFO:0007888	age at voice drop
EFO:0004682	QT interval
EFO:0009180	rosacea severity measurement
EFO:0004279	suntan
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0008328	chronotype measurement
EFO:0005670	smoking initiation
EFO:0004344	birth weight
EFO:0010098	stress-related disorder
EFO:0009458	alcohol use disorder measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004458	C-reactive protein measurement
EFO:0009749	age at first sexual intercourse measurement
EFO:0009101	age at first birth measurement
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL2093863 (PROTEIN FAMILY), CHEMBL2095153 (SELECTIVITY GROUP), CHEMBL2111340 (SELECTIVITY GROUP), CHEMBL2363066 (PROTEIN FAMILY), CHEMBL275 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

55 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 347,908 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL12856	INAMRINONE	4	9,690
CHEMBL1355736	THEOPHYLLINE	4	752
CHEMBL1520	VARDENAFIL	4	21,078
CHEMBL189	MILRINONE	4	20,605
CHEMBL191	LOSARTAN	4	88,932
CHEMBL192	SILDENAFIL	4	41,819
CHEMBL193240	ROFLUMILAST	4	19,604
CHEMBL249856	ENOXIMONE	4	5,206
CHEMBL4594287	ENSIFENTRINE	4	499
CHEMBL484785	CRISABOROLE	4	1,482
CHEMBL514800	APREMILAST	4	4,576
CHEMBL628	PENTOXIFYLLINE	4	26,061
CHEMBL779	TADALAFIL	4	23,417
CHEMBL932	DIPYRIDAMOLE	4	51,743
CHEMBL19449	IBUDILAST	4	7,461
CHEMBL332750	TETOMILAST	3	854
CHEMBL5095240	MUFEMILAST	3	103
CHEMBL511115	CILOMILAST	3	1,703
CHEMBL19224	PAPAVERINE	3	22,172
CHEMBL4541964	ZATOLMILAST	3	151
CHEMBL11417	STREPTONIGRIN	2
CHEMBL12831	IMAZODAN	2
CHEMBL17125	PELRINONE	2
CHEMBL2106994	PUMAFENTRINE	2
CHEMBL2107085	TOCLADESINE	2
CHEMBL2165191	AZD-6482	2
CHEMBL277465	DENBUFYLLINE	2
CHEMBL279898	ENPROFYLLINE	2
CHEMBL28079	ZAPRINAST	2
CHEMBL285913	TREQUINSIN	2

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs6421482	Toxicity	3	ethanol	Alcohol abuse

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12046844	PDE4B	3	0.00	1	gemcitabine
rs598961	PDE4B		0.00	0
rs17128809	PDE4B		0.00	0
rs6421482	PDE4B	3	1.50	1	ethanol
rs12745871	PDE4B		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Phosphodiesterases, 3’,5’-cyclic nucleotide (PDEs)

Most potent curated ligand interactions (13 total), top 13:

Ligand	Action	Affinity	Parameter
roflumilast	Inhibition	9.4	pIC50
PF-07038124	Inhibition	9.3	pIC50
MK-0359	Inhibition	9.3	pIC50
rolipram	Inhibition	9.0	pIC50
example 2 [WO2013026797A1]	Inhibition	8.14	pIC50
CDP840	Inhibition	8.07	pKi
nerandomilast	Inhibition	8.0	pIC50
apremilast	Inhibition	7.57	pIC50
ibudilast	Inhibition	7.19	pIC50
RS-25344	Inhibition	6.5	pIC50
Ro20-1724	Inhibition	6.4	pIC50
CBS-3595	Inhibition	5.72	pIC50
6-Hydroxy-5,7-dimethoxyflavone	Inhibition	5.07	pIC50

Binding affinities (BindingDB)

600 measured of 1060 human assays (1063 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-[3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-2-oxo-1H-imidazo[4,5-b]pyridin-6-yl]benzonitrile	IC50	0.234 nM	US-10662189: PDE4 inhibitor
5-chloro-2-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-6-(4-oxopentoxy)pyridine-3-carbonitrile	IC50	0.25 nM	US-8716478: Boron-containing small molecules
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-[2-(trifluoromethyl)phenyl]-1H-imidazo[4,5-b]pyridin-2-one	IC50	0.391 nM	US-10662189: PDE4 inhibitor
CHEMBL315565	IC50	0.398 nM
3-[(2S)-2-[3-cyclopropoxy-4-(difluoromethoxy)phenyl]-2-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]ethyl]-1-oxidopyridin-1-ium	IC50	0.4 nM
CHEMBL313982	IC50	0.501 nM
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-(2-ethylphenyl)-1H-imidazo[4,5-b]pyridin-2-one	IC50	0.515 nM	US-10662189: PDE4 inhibitor
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-(2-methoxyphenyl)-1H-imidazo[4,5-b]pyridin-2-one	IC50	0.641 nM	US-10662189: PDE4 inhibitor
6-(2,6-difluorophenyl)-3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1H-imidazo[4,5-b]pyridin-2-one	IC50	0.671 nM	US-10662189: PDE4 inhibitor
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-(2-fluorophenyl)-7-methyl-1H-imidazo[4,5-b]pyridin-2-one	IC50	0.685 nM	US-10662189: PDE4 inhibitor
5-chloro-6-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-2-(4-oxopentoxy)pyridine-3-carbonitrile	IC50	0.8 nM	US-8716478: Boron-containing small molecules
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-(2-ethoxyphenyl)-1H-imidazo[4,5-b]pyridin-2-one	IC50	0.861 nM	US-10662189: PDE4 inhibitor
2-[2-[4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxopyrazol-1-yl]piperidin-1-yl]-2-oxoethyl]isoindole-1,3-dione	IC50	0.87 nM	US-8865745: Pyrazolone derivatives as PDE4 inhibitors
6-(2,3-difluorophenyl)-3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1H-imidazo[4,5-b]pyridin-2-one	IC50	0.994 nM	US-10662189: PDE4 inhibitor
3-[1-[4-(difluoromethoxy)-3-ethoxyphenyl]-2-methylsulfonylethyl]-7-methyl-6-phenyl-1H-imidazo[4,5-b]pyridin-2-one	IC50	1.01 nM	US-10662189: PDE4 inhibitor
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-(2-propan-2-ylphenyl)-1H-imidazo[4,5-b]pyridin-2-one	IC50	1.04 nM	US-10662189: PDE4 inhibitor
6-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-2-(2-propan-2-yloxyethoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile	IC50	1.1 nM	US-8716478: Boron-containing small molecules
5-chloro-2-(2-cyclopropyloxyethoxy)-6-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]pyridine-3-carbonitrile	IC50	1.3 nM	US-8716478: Boron-containing small molecules
5-chloro-6-[(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)oxy]-2-(4-oxopentoxy)pyridine-3-carbonitrile	IC50	1.3 nM	US-8716478: Boron-containing small molecules
5-chloro-6-[(7-fluoro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-2-(4-oxopentoxy)pyridine-3-carbonitrile	IC50	1.7 nM	US-8716478: Boron-containing small molecules
3-[1-(3-ethoxy-4-methoxyphenyl)-3-methylsulfonylpropan-2-yl]-6-[(2-fluorophenyl)methyl]-1H-imidazo[4,5-b]pyridin-2-one	IC50	1.8 nM	US-10662189: PDE4 inhibitor
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-7-(2-fluorophenyl)-1H-imidazo[4,5-b]pyridin-2-one	IC50	1.87 nM	US-10662189: PDE4 inhibitor
5-chloro-6-[(1-hydroxy-7-methyl-3H-2,1-benzoxaborol-5-yl)oxy]-2-(2-propan-2-yloxyethoxy)pyridine-3-carbonitrile	IC50	2 nM	US-8716478: Boron-containing small molecules
6-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-2-(4-oxopentoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile	IC50	2.2 nM	US-8716478: Boron-containing small molecules
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-7-methyl-6-phenyl-1H-imidazo[4,5-b]pyridin-2-one	IC50	2.23 nM	US-10662189: PDE4 inhibitor
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-7-[(2-methylphenyl)methyl]-1H-imidazo[4,5-b]pyridin-2-one	IC50	2.24 nM	US-10662189: PDE4 inhibitor
3-(4-Chloro-3-fluorophenyl)-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide (7)	IC50	2.35 nM	US-10077269: Imidazopyridazine compounds
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-7-phenyl-1H-imidazo[4,5-b]pyridin-2-one	IC50	2.48 nM	US-10662189: PDE4 inhibitor
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-[2-(trifluoromethyl)phenoxy]-1H-imidazo[4,5-b]pyridin-2-one	IC50	2.53 nM	US-10662189: PDE4 inhibitor
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-phenyl-1H-imidazo[4,5-b]pyridin-2-one	IC50	2.6 nM	US-10662189: PDE4 inhibitor
3-[1-(3-ethoxy-4-methoxyphenyl)-3-methylsulfonylpropan-2-yl]-6-(3-methylbut-2-enyl)-1H-imidazo[4,5-b]pyridin-2-one	IC50	2.81 nM	US-10662189: PDE4 inhibitor
2-[1-(2-chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4-methyl-4-propylpyrazol-3-one	IC50	2.95 nM	US-8865745: Pyrazolone derivatives as PDE4 inhibitors
6-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-2-(4-oxopentoxy)pyridine-3-carbonitrile	IC50	3.1 nM	US-9499570: Boron containing small molecules
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-(1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-one	IC50	3.38 nM	US-10662189: PDE4 inhibitor
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-(3-fluorophenyl)-1H-imidazo[4,5-b]pyridin-2-one	IC50	3.4 nM	US-10662189: PDE4 inhibitor
6-bromo-3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1H-imidazo[4,5-b]pyridin-2-one	IC50	3.4 nM	US-10662189: PDE4 inhibitor
4-[2-[4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxopyrazol-1-yl]piperidin-1-yl]-2-oxoethyl]-1,1-dioxo-1,4-thiazinane-3,5-dione	IC50	3.8 nM	US-8865745: Pyrazolone derivatives as PDE4 inhibitors
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-(4-fluorophenyl)-1H-imidazo[4,5-b]pyridin-2-one	IC50	3.9 nM	US-10662189: PDE4 inhibitor
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-pyrimidin-2-yl-1H-imidazo[4,5-b]pyridin-2-one	IC50	4.51 nM	US-10662189: PDE4 inhibitor
3-[1-(3-ethoxy-4-methoxyphenyl)-3-methylsulfonylpropan-2-yl]-6-(2-methylpropyl)-1H-imidazo[4,5-b]pyridin-2-one	IC50	4.89 nM	US-10662189: PDE4 inhibitor
6-cyclopropyl-3-[1-(3-ethoxy-4-methoxyphenyl)-3-methylsulfonylpropan-2-yl]-1H-imidazo[4,5-b]pyridin-2-one	IC50	5.03 nM	US-10662189: PDE4 inhibitor
4-[2-[4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxopyrazol-1-yl]piperidin-1-yl]-2-oxoethyl]morpholine-3,5-dione	IC50	5.13 nM	US-8865745: Pyrazolone derivatives as PDE4 inhibitors
6-(4,6-dimethylpyrimidin-5-yl)-3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1H-imidazo[4,5-b]pyridin-2-one	IC50	5.18 nM	US-10662189: PDE4 inhibitor
5-chloro-6-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]-2-(2-propan-2-yloxyethoxy)pyridine-3-carbonitrile	IC50	5.2 nM	US-9499570: Boron containing small molecules
4-[2-[4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxopyrazol-1-yl]piperidin-1-yl]-2-oxoethyl]thiomorpholine-3,5-dione	IC50	5.37 nM	US-8865745: Pyrazolone derivatives as PDE4 inhibitors
3-[1-[4-(difluoromethoxy)-3-ethoxyphenyl]-2-methylsulfonylethyl]-6,7-dimethyl-1H-imidazo[4,5-b]pyridin-2-one	IC50	5.39 nM	US-10662189: PDE4 inhibitor
3-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-6-pyrimidin-2-yloxy-1H-imidazo[4,5-b]pyridin-2-one	IC50	5.42 nM	US-10662189: PDE4 inhibitor
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-[(1-methylpiperidin-4-yl)methoxy]-2-oxo-1-phenylethyl]amino]methyl]thiophene-2-carboxylate	IC50	5.5 nM	US-9636336: Aminoester derivatives
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-[[(3S)-1-methylpyrrolidin-3-yl]methoxy]-2-oxo-1-phenylethyl]amino]methyl]thiophene-2-carboxylate	IC50	5.5 nM	US-9636336: Aminoester derivatives
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-hydroxy-1-[(1-methylpiperidin-4-yl)methoxy]-1-oxo-2-phenylpropan-2-yl]amino]methyl]thiophene-2-carboxylate	IC50	5.5 nM	US-9636336: Aminoester derivatives

ChEMBL bioactivities

4686 potent at pChembl≥5 of 5301 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL3287987
11.00	IC50	0.01	nM	CHEMBL4744560
11.00	IC50	0.01	nM	CHEMBL4794267
11.00	IC50	0.01	nM	CHEMBL569791
10.85	IC50	0.014	nM	CHEMBL3986586
10.80	IC50	0.01585	nM	CHEMBL3287739
10.80	IC50	0.01585	nM	CHEMBL3287991
10.80	IC50	0.01585	nM	CHEMBL3287995
10.70	IC50	0.01995	nM	CHEMBL3287990
10.70	IC50	0.01995	nM	CHEMBL3287994
10.70	IC50	0.01995	nM	CHEMBL3287999
10.70	IC50	0.01995	nM	CHEMBL3288024
10.70	IC50	0.01995	nM	CHEMBL3288027
10.70	IC50	0.01995	nM	CHEMBL3288030
10.70	IC50	0.01995	nM	CHEMBL571381
10.70	IC50	0.02	nM	CHEMBL1830791
10.60	IC50	0.02512	nM	CHEMBL3288010
10.60	IC50	0.02512	nM	CHEMBL3287988
10.60	IC50	0.02512	nM	CHEMBL3288000
10.60	IC50	0.02512	nM	CHEMBL3288012
10.60	IC50	0.02512	nM	CHEMBL3288029
10.59	IC50	0.026	nM	TRANIMILAST
10.56	IC50	0.0278	nM	CHEMBL4075951
10.52	IC50	0.03	nM	CHEMBL2012227
10.52	IC50	0.03	nM	CHEMBL3113966
10.52	IC50	0.03	nM	CHEMBL3113954
10.52	IC50	0.03	nM	CHEMBL3113949
10.52	IC50	0.03	nM	CHEMBL3113948
10.52	IC50	0.03	nM	CHEMBL3746046
10.52	IC50	0.03	nM	CHEMBL3919325
10.52	IC50	0.03	nM	CHEMBL3913876
10.52	IC50	0.03	nM	CHEMBL3957127
10.52	IC50	0.03	nM	CHEMBL3968147
10.52	IC50	0.03	nM	CHEMBL3952586
10.52	IC50	0.03	nM	CHEMBL380321
10.50	IC50	0.03162	nM	CHEMBL3287989
10.50	IC50	0.03162	nM	CHEMBL3287993
10.50	IC50	0.03162	nM	CHEMBL3287997
10.50	IC50	0.03162	nM	CHEMBL3288001
10.50	IC50	0.03162	nM	CHEMBL3288016
10.50	IC50	0.03162	nM	CHEMBL3288022
10.50	IC50	0.03162	nM	CHEMBL3288025
10.40	IC50	0.04	nM	CHEMBL2012232
10.40	IC50	0.04	nM	CHEMBL3113943
10.40	IC50	0.04	nM	CHEMBL3113976
10.40	IC50	0.04	nM	TRANIMILAST
10.40	IC50	0.04	nM	CHEMBL3113968
10.40	IC50	0.04	nM	CHEMBL3113962
10.40	IC50	0.03981	nM	CHEMBL3288009
10.40	IC50	0.03981	nM	CHEMBL3288028

PubChem BioAssay actives

3605 with measured affinity, of 6100 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[[3-[6-(2-cyanopropan-2-yl)quinolin-8-yl]phenyl]methyl]-1-(4-methylsulfonylphenyl)-3-phenylurea	264624: Inhibition of human GST-PDE4B	ic50	<0.0001	uM
4-(3-methoxyanilino)-6-(4-methoxyphenyl)sulfonyl-8-methylquinoline-3-carboxamide	448555: Inhibition of human recombinant PDE4B by scintillation proximity assay	ic50	<0.0001	uM
8-(3,5-dichloroanilino)-4-methyl-5-methylsulfonyl-2,6,7,11-tetrazatricyclo[7.4.0.03,7]trideca-1,3,5,8-tetraen-10-one	1268774: Inhibition of human recombinant PDE4B1 expressed in insect Sf9 cells by fluorescence capillary-electrophoresis assay	ic50	<0.0001	uM
3-cyclopentyloxy-N-(3,5-dichloro-4-pyridinyl)-4-methoxybenzamide	1625374: Inhibition of human His-tagged PDE4B catalytic domain expressed in Escherichia coli BL21-CodonPlus(DE3) cells using [3H]cAMP or [3H]cGMP as substrate incubated for 30 mins by scintillation counting method	ic50	<0.0001	uM
5-[(1R)-1-aminoethyl]-N-(1-benzofuran-3-ylmethyl)-2-[8-methoxy-2-(trifluoromethyl)quinolin-5-yl]-1,3-oxazole-4-carboxamide	1720023: Inhibition of recombinant human PDE4B2 using cAMP as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by Alphascreen assay	ic50	<0.0001	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3-ethoxy-4-methoxyphenyl)ethyl] 5-[[[(2S)-1-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-3-hydroxy-1-oxo-2-phenylpropan-2-yl]amino]methyl]thiophene-2-carboxylate	2011004: Inhibition of human recombinant PDE4B2 expressed in baculovirus expression system using cAMP as substrate by radiometric assay	ic50	<0.0001	uM
N-[4-[(1,5-dimethylpyrazole-3-carbonyl)amino]cyclohexyl]-5-fluoro-2-[3-[4-hydroxy-2-(1,4-oxazepan-4-ylmethyl)phenyl]phenoxy]pyridine-3-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
2-[3-[4-[[(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl]phenyl]phenoxy]-N-[4-[(1,5-dimethylpyrazole-3-carbonyl)amino]cyclohexyl]-5-fluoropyridine-3-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
N-[4-[(1,5-dimethylpyrazole-3-carbonyl)amino]cyclohexyl]-5-fluoro-2-[3-[4-[2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]phenyl]phenoxy]pyridine-3-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
N-[4-[(1,5-dimethylpyrazole-3-carbonyl)amino]cyclohexyl]-5-fluoro-2-[3-[4-hydroxy-2-(morpholin-4-ylmethyl)phenyl]phenoxy]pyridine-3-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
6-[3-(dimethylcarbamoyl)phenyl]sulfonyl-4-(3-methoxyanilino)quinoline-3-carboxamide	448555: Inhibition of human recombinant PDE4B by scintillation proximity assay	ic50	<0.0001	uM
N-cyclopropyl-3-[3-[5-[(3,5-dichloro-4-pyridinyl)carbamoylamino]-1-ethyl-6-oxopyridazin-3-yl]phenyl]benzamide	1324554: Inhibition of human recombinant PDE4B1 assessed as reduction in [3H]cAMP hydrolysis to [3H]AMP incubated for 60 mins by PDE-SPA assay	ic50	<0.0001	uM
3-[3-[5-[(3,5-dichloro-4-pyridinyl)carbamoylamino]-1-ethyl-6-oxopyridazin-3-yl]phenyl]-N-(2-morpholin-4-ylethyl)benzamide	1324554: Inhibition of human recombinant PDE4B1 assessed as reduction in [3H]cAMP hydrolysis to [3H]AMP incubated for 60 mins by PDE-SPA assay	ic50	<0.0001	uM
1-(3,5-dichloro-4-pyridinyl)-3-[2-ethyl-6-[3-(2-fluoro-4-hydroxyphenyl)phenyl]-3-oxopyridazin-4-yl]urea	1324554: Inhibition of human recombinant PDE4B1 assessed as reduction in [3H]cAMP hydrolysis to [3H]AMP incubated for 60 mins by PDE-SPA assay	ic50	<0.0001	uM
3-[3-[5-[(3,5-dichloro-4-pyridinyl)carbamoylamino]-1-ethyl-6-oxopyridazin-3-yl]phenyl]-N-[7-[2-hydroxyethyl(methyl)amino]heptyl]benzamide	1324554: Inhibition of human recombinant PDE4B1 assessed as reduction in [3H]cAMP hydrolysis to [3H]AMP incubated for 60 mins by PDE-SPA assay	ic50	<0.0001	uM
N-cyclopropyl-3-[3-[4-[(1-hydroxyquinolin-5-ylidene)amino]-5-oxo-7,8-dihydro-6H-1,6-naphthyridin-2-yl]phenyl]benzamide	1455726: Inhibition of recombinant human PDE4B1 using [3H]-cAMP as substrate preincubated for 15 mins followed substrate addition measured after 60 mins by scintillation proximity assay	ic50	<0.0001	uM
8-N-(3,5-dichloro-4-pyridinyl)-4,4-dimethyl-13-N-(pyridin-3-ylmethyl)-11-oxa-9,14,16-triazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2(7),8,12(17),13,15-hexaene-8,13-diamine	619272: Inhibition of human PDE4B1 assessed as inhibition of [3H]cAMP hydrolysis to [3H]AMP after 15 mins by scintillation proximity assay	ic50	<0.0001	uM
5-[(1S)-1-aminoethyl]-N-[(2-chloro-6-fluorophenyl)methyl]-2-[8-methoxy-2-(trifluoromethyl)quinolin-5-yl]-1,3-oxazole-4-carboxamide	652939: Inhibition of PDE4B	ic50	<0.0001	uM
5-[(1S)-1-aminoethyl]-2-[8-methoxy-2-(trifluoromethyl)quinolin-5-yl]-N-[(2,4,6-trifluorophenyl)methyl]-1,3-oxazole-4-carboxamide	652939: Inhibition of PDE4B	ic50	<0.0001	uM
2-[3-[2-[(dimethylamino)methyl]-4-hydroxyphenyl]phenoxy]-5-fluoro-N-[4-[(6-methylpyridine-2-carbonyl)amino]cyclohexyl]pyridine-3-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
5-fluoro-N-[4-[[1-methyl-5-(trifluoromethyl)pyrazole-3-carbonyl]amino]cyclohexyl]-2-[3-[4-(3-piperazin-1-ylpropyl)phenyl]phenoxy]pyridine-3-carboxamide	1720040: Inhibition of recombinant human PDE4B2 preincubated for 30 mins followed by [3H]cyclic AMP addition and measured after 20 mins by radiometric assay	ic50	<0.0001	uM
N-[4-[[5-fluoro-2-[3-[4-hydroxy-2-(1,4-oxazepan-4-ylmethyl)phenyl]phenoxy]pyridine-3-carbonyl]amino]cyclohexyl]-5-methylimidazo[1,2-a]pyridine-2-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
2-[3-[4-[[(3S,5R)-3,5-dimethylpiperazin-1-yl]methyl]-3-hydroxyphenyl]phenoxy]-N-[4-[(1,5-dimethylpyrazole-3-carbonyl)amino]cyclohexyl]-5-fluoropyridine-3-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
6-fluoro-N-[4-[[5-fluoro-2-[3-[4-hydroxy-2-(1,4-oxazepan-4-ylmethyl)phenyl]phenoxy]pyridine-3-carbonyl]amino]cyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
N-[4-[[5-fluoro-2-[3-[4-hydroxy-2-(morpholin-4-ylmethyl)phenyl]phenoxy]pyridine-3-carbonyl]amino]cyclohexyl]-4-methyl-1,3-thiazole-2-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
2-[3-[3-[[(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl]-4-hydroxyphenyl]phenoxy]-N-[4-[(1,5-dimethylpyrazole-3-carbonyl)amino]cyclohexyl]-5-fluoropyridine-3-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
N-[4-[[5-fluoro-2-[3-[4-hydroxy-2-(1,4-oxazepan-4-ylmethyl)phenyl]phenoxy]pyridine-3-carbonyl]amino]cyclohexyl]-2-methyl-1,3-thiazole-4-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
2-[3-[4-[[(3S,5R)-3,5-dimethylpiperazin-1-yl]methyl]-2-(morpholin-4-ylmethyl)phenyl]phenoxy]-5-fluoro-N-[4-[(2-hydroxy-5-methylbenzoyl)amino]cyclohexyl]pyridine-3-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
2-[3-[3-[[(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl]-5-hydroxyphenyl]phenoxy]-N-[4-[(1,5-dimethylpyrazole-3-carbonyl)amino]cyclohexyl]-5-fluoropyridine-3-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
N-[4-[[5-fluoro-2-[3-[4-hydroxy-2-(morpholin-4-ylmethyl)phenyl]phenoxy]pyridine-3-carbonyl]amino]cyclohexyl]-5-methylimidazo[1,2-a]pyridine-2-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
N-[4-[[5-fluoro-2-[3-[4-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]phenyl]phenoxy]pyridine-3-carbonyl]amino]cyclohexyl]-5-methylimidazo[1,2-a]pyridine-2-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
N-[4-[[2-[3-[2-[(dimethylamino)methyl]-4-hydroxyphenyl]phenoxy]-5-fluoropyridine-3-carbonyl]amino]cyclohexyl]-2-methyl-1,3-thiazole-4-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
5-fluoro-2-[3-[4-hydroxy-2-(1,4-oxazepan-4-ylmethyl)phenyl]phenoxy]-N-[4-[(6-methylpyridine-2-carbonyl)amino]cyclohexyl]pyridine-3-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
N-[4-[[5-fluoro-2-[3-[4-hydroxy-2-(morpholin-4-ylmethyl)phenyl]phenoxy]pyridine-3-carbonyl]amino]cyclohexyl]-2-methyl-1,3-thiazole-4-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
N-[4-[[2-[3-[4-[[(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl]-2-(morpholin-4-ylmethyl)phenyl]phenoxy]-5-fluoropyridine-3-carbonyl]amino]cyclohexyl]-4-methyl-1,3-thiazole-2-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
N-[4-[[2-[3-[4-[[(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl]phenyl]phenoxy]-5-fluoropyridine-3-carbonyl]amino]cyclohexyl]pyrazolo[1,5-a]pyridine-2-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
2-[3-[4-[3-[(3S,5R)-3,5-dimethylpiperazin-1-yl]propyl]phenyl]phenoxy]-N-[4-[(1,5-dimethylpyrazole-3-carbonyl)amino]cyclohexyl]-5-fluoropyridine-3-carboxamide	1152014: Inhibition of human recombinant PDE4B using [3H]cAMP by packard topcount scintillation counting analysis	ic50	<0.0001	uM
2-[4-[3-[5-[(3,5-dichloro-4-pyridinyl)carbamoylamino]-1-ethyl-6-oxopyridazin-3-yl]phenyl]phenyl]-N-[7-[2-hydroxyethyl(methyl)amino]heptyl]acetamide	1324554: Inhibition of human recombinant PDE4B1 assessed as reduction in [3H]cAMP hydrolysis to [3H]AMP incubated for 60 mins by PDE-SPA assay	ic50	<0.0001	uM
2-[3-[3-[5-[(3,5-dichloro-4-pyridinyl)carbamoylamino]-1-ethyl-6-oxopyridazin-3-yl]phenyl]phenyl]acetic acid	1324554: Inhibition of human recombinant PDE4B1 assessed as reduction in [3H]cAMP hydrolysis to [3H]AMP incubated for 60 mins by PDE-SPA assay	ic50	<0.0001	uM
methyl 3-[3-[5-[(3,5-dichloro-4-pyridinyl)carbamoylamino]-1-ethyl-6-oxopyridazin-3-yl]phenyl]-5-[3-(dimethylamino)propylcarbamoyl]benzoate	1324554: Inhibition of human recombinant PDE4B1 assessed as reduction in [3H]cAMP hydrolysis to [3H]AMP incubated for 60 mins by PDE-SPA assay	ic50	<0.0001	uM
5-[3-[5-[(3,5-dichloro-4-pyridinyl)carbamoylamino]-1-ethyl-6-oxopyridazin-3-yl]phenyl]-3-N-(2-hydroxyethyl)-1-N-(2-piperidin-1-ylethyl)benzene-1,3-dicarboxamide	1324554: Inhibition of human recombinant PDE4B1 assessed as reduction in [3H]cAMP hydrolysis to [3H]AMP incubated for 60 mins by PDE-SPA assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(cyclopropylmethoxy)-4-(methanesulfonamido)benzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(methanesulfonamido)-4-methylbenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] (2S)-3-[3-(dimethylcarbamoyl)phenyl]sulfonyl-1,3-thiazolidine-2-carboxylate	1472212: Inhibition of human recombinant PDE4B expressed insect sf9 cells by radiometric assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] (2S)-1-[3-(dimethylcarbamoyl)phenyl]sulfonylpyrrolidine-2-carboxylate	2010973: Inhibition of human recombinant PDE4B2 expressed in baculovirus expression system using cAMP as substrate incubated for 2 hrs by HTRF assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(cyclopropylmethoxy)-4-methoxybenzoate	1068845: Inhibition of PDE4 activity in human PBMC assessed as inhibition of LPS-induced TNFalpha release after 18 hrs by ELISA	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(dimethylsulfamoyl)-4-methoxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(cyclopropylmethoxy)-4-hydroxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-(hydroxymethyl)-4-(methanesulfonamido)benzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 5-(methanesulfonamido)-2-methoxybenzoate	1068846: Inhibition of PDE4 isolated from human U937 cells assessed as reduction in cAMP level by LANCE assay	ic50	<0.0001	uM

CTD chemical–gene interactions

89 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression, affects expression	6
(+)-JQ1 compound	decreases expression, decreases reaction	4
Estradiol	affects expression, affects binding, increases expression, affects cotreatment, decreases expression	4
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	3
Formaldehyde	decreases expression, increases expression	3
Lipopolysaccharides	increases expression, affects expression, affects reaction, decreases reaction	3
sulforaphane	decreases expression, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
nickel sulfate	increases expression	2
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression, decreases expression	2
entinostat	affects cotreatment, decreases expression	2
Roflumilast	increases expression, decreases activity, decreases reaction	2
Decitabine	affects expression, affects cotreatment	2
Cyclic AMP	decreases reaction, decreases activity, increases abundance, affects binding	2
Arsenic	increases abundance, decreases expression, affects cotreatment	2
Calcitriol	increases expression	2
Cisplatin	affects expression, increases expression	2
Nickel	increases expression	2
Progesterone	increases expression, decreases expression	2
Tretinoin	increases expression, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
FR900359	increases phosphorylation	1
N(6)-(delta(2)-isopentenyl)adenine	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
ferrous chloride	decreases expression	1

ChEMBL screening assays

796 unique, capped per target: 755 binding, 29 functional, 11 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000405	Binding	Inhibition of PDE4 in human lung	Recent advances on phosphodiesterase 4 inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. — J Med Chem
CHEMBL4348839	ADMET	Inhibition of PDE4 (unknown origin)	Structure Overhaul Affords a Potent Purine PI3Kδ Inhibitor with Improved Tolerability. — J Med Chem
CHEMBL682878	Functional	PDE4-related emetic activity in ferrets after intravenous administration at 10 mg/kg	Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6, 7,1-hi]indoles: discovery of potent, selective phosphodiesterase type 4 inhibitors. — J Med Chem

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2A8	Abcam HeLa PDE4B KO	Cancer cell line	Female
CVCL_C0U3	ACTOne cAMP-PDE4B	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.