Target Information
| Target General Information | Top | |||||
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| Target ID |
T61744
(Former ID: TTDS00280)
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| Target Name |
Phosphodiesterase 4A (PDE4A)
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| Synonyms |
cAMP-specific 3',5'-cyclic phosphodiesterase 4A; Type 4A cAMP phosphodiesterase; PDE46; DPDE2
Click to Show/Hide
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| Gene Name |
PDE4A
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Asthma [ICD-11: CA23] | |||||
| Function |
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Click to Show/Hide
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| BioChemical Class |
Phosphoric diester hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.1.4.53
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| Sequence |
MEPPTVPSERSLSLSLPGPREGQATLKPPPQHLWRQPRTPIRIQQRGYSDSAERAERERQ
PHRPIERADAMDTSDRPGLRTTRMSWPSSFHGTGTGSGGAGGGSSRRFEAENGPTPSPGR SPLDSQASPGLVLHAGAATSQRRESFLYRSDSDYDMSPKTMSRNSSVTSEAHAEDLIVTP FAQVLASLRSVRSNFSLLTNVPVPSNKRSPLGGPTPVCKATLSEETCQQLARETLEELDW CLEQLETMQTYRSVSEMASHKFKRMLNRELTHLSEMSRSGNQVSEYISTTFLDKQNEVEI PSPTMKEREKQQAPRPRPSQPPPPPVPHLQPMSQITGLKKLMHSNSLNNSNIPRFGVKTD QEELLAQELENLNKWGLNIFCVSDYAGGRSLTCIMYMIFQERDLLKKFRIPVDTMVTYML TLEDHYHADVAYHNSLHAADVLQSTHVLLATPALDAVFTDLEILAALFAAAIHDVDHPGV SNQFLINTNSELALMYNDESVLENHHLAVGFKLLQEDNCDIFQNLSKRQRQSLRKMVIDM VLATDMSKHMTLLADLKTMVETKKVTSSGVLLLDNYSDRIQVLRNMVHCADLSNPTKPLE LYRQWTDRIMAEFFQQGDRERERGMEISPMCDKHTASVEKSQVGFIDYIVHPLWETWADL VHPDAQEILDTLEDNRDWYYSAIRQSPSPPPEEESRGPGHPPLPDKFQFELTLEEEEEEE ISMAQIPCTAQEALTAQGLSGVEEALDATIAWEASPAQESLEVMAQEASLEAELEAVYLT QQAQSTGSAPVAPDEFSSREEFVVAVSHSSPSALALQSPLLPAWRTLSVSEHAPGLPGLP STAAEVEAQREHQAAKRACSACAGTFGEDTSALPAPGGGGSGGDPT Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T95GWW | |||||
| Drugs and Modes of Action | Top | |||||
|---|---|---|---|---|---|---|
| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Dyphylline | Drug Info | Approved | Acute bronchial asthma | [2], [3], [4] | |
| 2 | Enprofylline | Drug Info | Approved | Asthma | [5] | |
| Clinical Trial Drug(s) | [+] 20 Clinical Trial Drugs | + | ||||
| 1 | DENBUFYLLINE | Drug Info | Phase 3 | Cognitive impairment | [6] | |
| 2 | SOTB07 | Drug Info | Phase 3 | Asthma | [7] | |
| 3 | AN-2898 | Drug Info | Phase 2 | Atopic dermatitis | [8] | |
| 4 | AWD-12-281 | Drug Info | Phase 2 | Rhinitis | [9] | |
| 5 | CC-1088 | Drug Info | Phase 2 | Crohn disease | [10] | |
| 6 | GPD-1116 | Drug Info | Phase 2 | Asthma | [11] | |
| 7 | HT-0712 | Drug Info | Phase 2 | Cognitive impairment | [12] | |
| 8 | LIRIMILAST | Drug Info | Phase 2 | Chronic obstructive pulmonary disease | [13] | |
| 9 | MK-0873 | Drug Info | Phase 2 | Psoriasis vulgaris | [14] | |
| 10 | Oglemilast | Drug Info | Phase 2 | Asthma | [15] | |
| 11 | OX-914 | Drug Info | Phase 2 | Asthma | [16] | |
| 12 | Piclamilast | Drug Info | Phase 2 | Rheumatoid arthritis | [17] | |
| 13 | Revamilast | Drug Info | Phase 2 | Asthma | [18] | |
| 14 | TA-7906 | Drug Info | Phase 2 | Atopic dermatitis | [19] | |
| 15 | TOFIMILAST | Drug Info | Phase 2 | Chronic obstructive pulmonary disease | [20] | |
| 16 | Tofisopam | Drug Info | Phase 2 | Irritable bowel syndrome | [21] | |
| 17 | AVE-8112 | Drug Info | Phase 1 | Parkinson disease | [22] | |
| 18 | GSK-356278 | Drug Info | Phase 1 | Huntington disease | [23] | |
| 19 | MEM-1414 | Drug Info | Phase 1 | Mood disorder | [24] | |
| 20 | Ronomilast | Drug Info | Phase 1 | Chronic obstructive pulmonary disease | [25] | |
| Discontinued Drug(s) | [+] 16 Discontinued Drugs | + | ||||
| 1 | Cilomilast | Drug Info | Discontinued in Phase 3 | Chronic obstructive pulmonary disease | [26], [27] | |
| 2 | CDP840 | Drug Info | Discontinued in Phase 2 | Chronic obstructive pulmonary disease | [28] | |
| 3 | CI-1018 | Drug Info | Discontinued in Phase 2 | Asthma | [29] | |
| 4 | Daxalipram | Drug Info | Discontinued in Phase 2 | Multiple sclerosis | [30] | |
| 5 | GSK256066 | Drug Info | Discontinued in Phase 2 | Asthma | [31] | |
| 6 | KW-4490 | Drug Info | Discontinued in Phase 2 | Asthma | [32] | |
| 7 | LAS-37779 | Drug Info | Discontinued in Phase 2 | Psoriasis vulgaris | [33] | |
| 8 | V-11294A | Drug Info | Discontinued in Phase 2 | Asthma | [34] | |
| 9 | D-4418 | Drug Info | Discontinued in Phase 1 | Cutaneous T-cell lymphoma | [35] | |
| 10 | SCH-351591 | Drug Info | Discontinued in Phase 1 | Chronic obstructive pulmonary disease | [36] | |
| 11 | YM-976 | Drug Info | Discontinued in Phase 1 | Asthma | [37], [38] | |
| 12 | D-22888 | Drug Info | Terminated | Allergy | [39] | |
| 13 | GW-3600 | Drug Info | Terminated | Asthma | [40] | |
| 14 | NIK-616 | Drug Info | Terminated | Chronic obstructive pulmonary disease | [41] | |
| 15 | TJN-598 | Drug Info | Terminated | Glomerulonephritis | [42] | |
| 16 | Torbafylline | Drug Info | Terminated | Peripheral vascular disease | [43] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 80 Inhibitor drugs | + | ||||
| 1 | Dyphylline | Drug Info | [1] | |||
| 2 | Enprofylline | Drug Info | [5] | |||
| 3 | DENBUFYLLINE | Drug Info | [44] | |||
| 4 | SOTB07 | Drug Info | [45] | |||
| 5 | AN-2898 | Drug Info | [46] | |||
| 6 | AWD-12-281 | Drug Info | [47] | |||
| 7 | CC-1088 | Drug Info | [48] | |||
| 8 | GPD-1116 | Drug Info | [11] | |||
| 9 | HT-0712 | Drug Info | [45] | |||
| 10 | LIRIMILAST | Drug Info | [49] | |||
| 11 | MK-0873 | Drug Info | [50] | |||
| 12 | Oglemilast | Drug Info | [49] | |||
| 13 | OX-914 | Drug Info | [51] | |||
| 14 | Piclamilast | Drug Info | [52] | |||
| 15 | Revamilast | Drug Info | [53] | |||
| 16 | TA-7906 | Drug Info | [54] | |||
| 17 | TOFIMILAST | Drug Info | [55] | |||
| 18 | Tofisopam | Drug Info | [56] | |||
| 19 | AVE-8112 | Drug Info | [57] | |||
| 20 | GSK-356278 | Drug Info | [58] | |||
| 21 | MEM-1414 | Drug Info | [59] | |||
| 22 | Ronomilast | Drug Info | [60] | |||
| 23 | Cilomilast | Drug Info | [27] | |||
| 24 | CDP840 | Drug Info | [61] | |||
| 25 | CI-1018 | Drug Info | [62] | |||
| 26 | Daxalipram | Drug Info | [63] | |||
| 27 | GSK256066 | Drug Info | [64] | |||
| 28 | KW-4490 | Drug Info | [65] | |||
| 29 | LAS-37779 | Drug Info | [66] | |||
| 30 | V-11294A | Drug Info | [67] | |||
| 31 | D-4418 | Drug Info | [68] | |||
| 32 | SCH-351591 | Drug Info | [69] | |||
| 33 | YM-976 | Drug Info | [70] | |||
| 34 | D-22888 | Drug Info | [71] | |||
| 35 | GW-3600 | Drug Info | [72] | |||
| 36 | NIK-616 | Drug Info | [73] | |||
| 37 | TJN-598 | Drug Info | [42] | |||
| 38 | Torbafylline | Drug Info | [43] | |||
| 39 | (2,5-Diphenyl-furan-3-yl)-phenyl-methanone | Drug Info | [74] | |||
| 40 | (R)-Rolipram | Drug Info | [75] | |||
| 41 | (S)-Rolipram | Drug Info | [75] | |||
| 42 | 1-Butyl-3-methyl-3,7-dihydro-purine-2,6-dione | Drug Info | [76] | |||
| 43 | 1-Methyl-3-propyl-3,7-dihydro-purine-2,6-dione | Drug Info | [76] | |||
| 44 | 2,5-Bis-(3,4-dimethoxy-phenyl)-furan | Drug Info | [74] | |||
| 45 | 2,5-Bis-(3-cyclopentyloxy-4-methoxy-phenyl)-furan | Drug Info | [74] | |||
| 46 | 4-(2,5-Diphenyl-furan-3-yl)-morpholine | Drug Info | [74] | |||
| 47 | 6-Azido-8-(3-iodo-phenyl)-quinoline | Drug Info | [77] | |||
| 48 | 6-Imidazol-1-ylmethyl-8-phenyl-quinoline | Drug Info | [77] | |||
| 49 | 8-(3-Azido-phenyl)-6-iodo-quinoline | Drug Info | [77] | |||
| 50 | 8-(3-Azido-phenyl)-6-pyridin-4-ylmethyl-quinoline | Drug Info | [77] | |||
| 51 | 8-(3-Nitro-phenyl)-6-phenyl-[1,7]naphthyridine | Drug Info | [78] | |||
| 52 | 8-(3-Nitro-phenyl)-6-pyridin-4-ylmethyl-quinoline | Drug Info | [77] | |||
| 53 | AL-59640 | Drug Info | [45] | |||
| 54 | ASP-3258 | Drug Info | [45] | |||
| 55 | Benzyl-(2-imidazol-1-yl-quinazolin-4-yl)-amine | Drug Info | [79] | |||
| 56 | Benzyl-(2-phenyl-quinazolin-4-yl)-amine | Drug Info | [79] | |||
| 57 | Benzyl-(2-pyridin-3-yl-quinazolin-4-yl)-amine | Drug Info | [79] | |||
| 58 | Benzyl-(2-pyridin-4-yl-quinazolin-4-yl)-amine | Drug Info | [79] | |||
| 59 | Benzyl-(2-thiophen-2-yl-quinazolin-4-yl)-amine | Drug Info | [79] | |||
| 60 | CD-160130 | Drug Info | [45] | |||
| 61 | CH-3697 | Drug Info | [45] | |||
| 62 | CHF-5480 | Drug Info | [45] | |||
| 63 | CI-1044 | Drug Info | [80] | |||
| 64 | isobutylmethylxanthine | Drug Info | [81] | |||
| 65 | KF-66490 | Drug Info | [82] | |||
| 66 | KURAIDIN | Drug Info | [83] | |||
| 67 | KURARINOL | Drug Info | [83] | |||
| 68 | L-454560 | Drug Info | [84] | |||
| 69 | L-791943 | Drug Info | [85] | |||
| 70 | L-869298 | Drug Info | [86] | |||
| 71 | NIS-62949 | Drug Info | [87] | |||
| 72 | NITRAQUAZONE | Drug Info | [88] | |||
| 73 | OCID-2987 | Drug Info | [45] | |||
| 74 | ROLIPRAM | Drug Info | [89] | |||
| 75 | RS-14491 | Drug Info | [90] | |||
| 76 | RS-25344 | Drug Info | [91] | |||
| 77 | SOPHOFLAVESCENOL | Drug Info | [83] | |||
| 78 | TAS-203 | Drug Info | [45] | |||
| 79 | UCB-101333-3 | Drug Info | [92] | |||
| 80 | ZL-N-91 | Drug Info | [45] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: PMID28870136-Compound-49 | Ligand Info | |||||
| Structure Description | The structure of PDE4A with pentoxifylline at 2.84A resolution | PDB:3TVX | ||||
| Method | X-ray diffraction | Resolution | 2.84 Å | Mutation | No | [93] |
| PDB Sequence |
MNIPRFGVKT
298 DQEELLAQEL308 ENLNKWGLNI318 FCVSDYAGGR328 SLTCIMYMIF338 QERDLLKKFR 348 IPVDTMVTYM358 LTLEDHYHAD368 VAYHNSLHAA378 DVLQSTHVLL388 ATPALDAVFT 398 DLEILAALFA408 AAIHDVDHPG418 VSNQFLINTN428 SELALMYNDE438 SVLENHHLAV 448 GFKLLQEDNC458 DIFQNLSKRQ468 RQSLRKMVID478 MVLATDMSKH488 MTLLADLKTM 498 VETKKVTSSG508 VLLLDNYSDR518 IQVLRNMVHC528 ADLSNPTKPL538 ELYRQWTDRI 548 MAEFFQQGDR558 ERERGMEISP568 MCDKHTASVE578 KSQVGFIDYI588 VHPLWETWAD 598 LVHPDAQEIL608 DTLEDNRDWY618 YSAI
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| Ligand Name: (4r)-4-(3-Butoxy-4-Methoxybenzyl)imidazolidin-2-One | Ligand Info | |||||
| Structure Description | Crystal structure of human PDE4a with 4-(3-butoxy-4-methoxyphenyl)methyl-2-imidazolidone | PDB:3I8V | ||||
| Method | X-ray diffraction | Resolution | 2.25 Å | Mutation | No | [94] |
| PDB Sequence |
HMNIPRFGVK
297 TDQEELLAQE307 LENLNKWGLN317 IFVSDYAGGR328 SLTCIMYMIF338 QERDLLKKFR 348 IPVDTMVTYM358 LTLEDHYHAD368 VAYHNSLHAA378 DVLQSTHVLL388 ATPALDAVFT 398 DLEILAALFA408 AAIHDVDHPG418 VSNQFLINTN428 SELALMYNDE438 SVLENHHLAV 448 GFKLLQEDNC458 DIFQNLSKRQ468 RQSLRKMVID478 MVLATDMSKH488 MTLLADLKTM 498 VETKKVTSSG508 VLLLDNYSDR518 IQVLRNMVHC528 ADLSNPTKPL538 ELYRQWTDRI 548 MAEFFQQGDR558 ERERGMEISP568 MCDKHTASVE578 KSQVGFIDYI588 VHPLWETWAD 598 LVHPDAQEIL608 DTLEDNRDWY618 YSAI
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Purine metabolism | hsa00230 | Affiliated Target |
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| Class: Metabolism => Nucleotide metabolism | Pathway Hierarchy | ||
| cAMP signaling pathway | hsa04024 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Parathyroid hormone synthesis, secretion and action | hsa04928 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 4 | Degree centrality | 4.30E-04 | Betweenness centrality | 7.73E-05 |
|---|---|---|---|---|---|
| Closeness centrality | 2.00E-01 | Radiality | 1.35E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.18E+01 | Topological coefficient | 2.56E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
|---|---|---|---|---|---|---|
| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Purine metabolism | |||||
| 2 | cAMP signaling pathway | |||||
| 3 | Morphine addiction | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | DARPP-32 events | |||||
| 2 | G alpha (s) signalling events | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | G Protein Signaling Pathways | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
|---|---|---|---|---|---|---|
| REF 1 | Ocular hypotension induced by topical dopaminergic drugs and phosphodiesterase inhibitors. Eur J Pharmacol. 1994 Jun 2;258(1-2):85-94. | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7070). | |||||
| REF 3 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 4 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 007794. | |||||
| REF 5 | Effects of enprofylline, a new xanthine derivate, on human pregnant myometrium. Am J Obstet Gynecol. 1987 Apr;156(4):958-62. | |||||
| REF 6 | Denbufylline in dementia: a double-blind controlled study. Dement Geriatr Cogn Disord. 1999 Nov-Dec;10(6):505-10. | |||||
| REF 7 | ClinicalTrials.gov (NCT01907763) Study Phase III Study to Assess the Efficacy and Safety of SOTB07 in Asthma Patients. U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT01301508) Efficacy and Safety of AN2898 and AN2728 Topical Ointments to Treat Mild-to-Moderate Atopic Dermatitis. U.S. National Institutes of Health. | |||||
| REF 9 | ClinicalTrials.gov (NCT00354510) Topical GW842470X In Adults Patients With Moderate Atopic Dermatitis. U.S. National Institutes of Health. | |||||
| REF 10 | ClinicalTrials.gov (NCT00045786) Study to Determine the Safety and Preliminary Efficacy of CC-1088 in the Treatment of Myelodysplastic Syndromes. U.S. National Institutes of Health. | |||||
| REF 11 | Phosphodiesterase 4 inhibitor GPD-1116 markedly attenuates the development of cigarette smoke-induced emphysema in senescence-accelerated mice P1 s... Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L196-204. | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018324) | |||||
| REF 13 | A novel phosphodiesterase 4 inhibitor template. Expert Opinion on Therapeutic Patents,2003, 13(6), 929-933. | |||||
| REF 14 | ClinicalTrials.gov (NCT00132730) An Investigational Drug Study In Patients With COPD (Chronic Obstructive Pulmonary Disease) (MK-0873-005). U.S. National Institutes of Health. | |||||
| REF 15 | ClinicalTrials.gov (NCT00671073) Study To Assess Efficacy and Safety of Oglemilast in Patients With Chronic Obstructive Pulmonary Disease (COPD). U.S. National Institutes of Health. | |||||
| REF 16 | ClinicalTrials.gov (NCT00758446) Efficacy and Safety Study of BLX-028914 in Subjects With Allergic Rhinitis. U.S. National Institutes of Health. | |||||
| REF 17 | Effect of food and gender on the pharmacokinetics of RP 73401, a phosphodiesterase IV inhibitor. Int J Clin Pharmacol Ther. 2000 Dec;38(12):588-94. | |||||
| REF 18 | ClinicalTrials.gov (NCT01436890) A Clinical Trial to Study the Effects of Revamilast in Patients With Chronic Persistent Asthma. U.S. National Institutes of Health. | |||||
| REF 19 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024588) | |||||
| REF 20 | ClinicalTrials.gov (NCT00150397) A Study of the Safety and Efficacy of Tofimilast in Adult Asthmatics. U.S. National Institutes of Health. | |||||
| REF 21 | ClinicalTrials.gov (NCT00486876) A Study of 3 Doses of Dextofisopam in Females With Irritable Bowel Syndrome. U.S. National Institutes of Health. | |||||
| REF 22 | ClinicalTrials.gov (NCT01803945) A Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AVE8112 in Patients With Parkinson's Disease. U.S. National Institutes of Health. | |||||
| REF 23 | ClinicalTrials.gov (NCT01031186) First Time in Human Study. U.S. National Institutes of Health. | |||||
| REF 24 | The Quest for Human Longevity, Lewis D. Solo. Page(145). | |||||
| REF 25 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013990) | |||||
| REF 26 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7407). | |||||
| REF 27 | Emerging drugs for asthma. Expert Opin Emerg Drugs. 2008 Dec;13(4):643-53. | |||||
| REF 28 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003087) | |||||
| REF 29 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010034) | |||||
| REF 30 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015672) | |||||
| REF 31 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024245) | |||||
| REF 32 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017153) | |||||
| REF 33 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022894) | |||||
| REF 34 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800012597) | |||||
| REF 35 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007757) | |||||
| REF 36 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010874) | |||||
| REF 37 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5292). | |||||
| REF 38 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010783) | |||||
| REF 39 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007179) | |||||
| REF 40 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006447) | |||||
| REF 41 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020194) | |||||
| REF 42 | Effects of TJN-598, a new selective phosphodiesterase type IV inhibitor on anti-Thy1 nephritis in rats. Clin Exp Nephrol. 2011 Feb;15(1):14-24. | |||||
| REF 43 | Phosphodiesterase (PDE) inhibitor torbafylline (HWA 448) attenuates burn-induced rat skeletal muscle proteolysis through the PDE4/cAMP/EPAC/PI3K/Akt pathway. Mol Cell Endocrinol. 2014 Aug 5;393(1-2):152-63. | |||||
| REF 44 | Pyrazolopyrimidine-2,4-dione sulfonamides: novel and selective calcitonin inducers. J Med Chem. 2002 May 23;45(11):2342-5. | |||||
| REF 45 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1300). | |||||
| REF 46 | An assessment of the genetic toxicology of novel boron-containing therapeutic agents. Environ Mol Mutagen. 2013 Jun;54(5):338-46. | |||||
| REF 47 | The phosphodiesterase 4 inhibitor AWD 12-281 is active in a new guinea-pig model of allergic skin inflammation predictive of human skin penetration and suppresses both Th1 and Th2 cytokines in mice. J Pharm Pharmacol. 2005 Dec;57(12):1609-17. | |||||
| REF 48 | Thalidomide analogs and PDE4 inhibition. Bioorg Med Chem Lett. 1998 Oct 6;8(19):2669-74. | |||||
| REF 49 | Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking . Br J Pharmacol. 2008 October; 155(3): 288-290. | |||||
| REF 50 | MK-0873, a PDE4 inhibitor, does not influence the pharmacokinetics of theophylline in healthy male volunteers. Pulm Pharmacol Ther. 2008;21(3):573-7. | |||||
| REF 51 | Orexo announces Phase IIa data on OX914 in rhinitis. Orexo. 24th March, 2009. | |||||
| REF 52 | Effects of piclamilast, a selective phosphodiesterase-4 inhibitor, on oxidative burst of sputum cells from mild asthmatics and stable COPD patients. Lung. 2004;182(6):369-77. | |||||
| REF 53 | WO patent application no. 2012,1109,46, Pharmaceutical composition comprising the pde4 enzyme inhibitor revamilast and a disease modifying agent, preferably methotrexate . | |||||
| REF 54 | Potential role of phosphodiesterase 7 in human T cell function: comparative effects of two phosphodiesterase inhibitors. Clin Exp Immunol. 2002 Jun;128(3):460-6. | |||||
| REF 55 | GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: in vitro, kinetic, and in vivo characterization. J Pharmacol Exp Ther. 2011 Apr;337(1):145-54. | |||||
| REF 56 | The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis. J Neural Transm (Vienna). 2010 Nov;117(11):1319-25. | |||||
| REF 57 | Therapy for Parkinson's Disease: What is in the Pipeline . Neurotherapeutics. 2014 January; 11(1): 24-33. | |||||
| REF 58 | GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species. J Pharmacol Exp Ther. 2014 Jul;350(1):153-63. | |||||
| REF 59 | The effect of the novel phosphodiesterase-4 inhibitor MEM 1414 on the allergen induced responses in mild asthma. BMC Pulm Med. 2014 Oct 28;14:166. | |||||
| REF 60 | Clinical pipeline report, company report or official report of Avarx. | |||||
| REF 61 | Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: structure-activity relationship, optimization, and identification of a highly... Bioorg Med Chem Lett. 2005 Dec 1;15(23):5241-6. | |||||
| REF 62 | New substituted triaza-benzo[cd]azulen-9-ones as promising phosphodiesterase-4 inhibitors. Bioorg Med Chem Lett. 2004 Jun 21;14(12):3303-6. | |||||
| REF 63 | Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice. Front Neurosci. 2014 May 27;8:129. | |||||
| REF 64 | Clinical pipeline report, company report or official report of GlaxoSmithKline (2009). | |||||
| REF 65 | Pharmacokinetics and metabolism of KW-4490, a selective phosphodiesterase 4 inhibitor: difference in excretion of KW-4490 and acylglucuronide metabolites between rats and cynomolgus monkeys. Xenobiotica. 2008 May;38(5):511-26. | |||||
| REF 66 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022894) | |||||
| REF 67 | Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers. Br J Clin Pharmacol. 2002 Nov;54(5):478-84. | |||||
| REF 68 | Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking. Br J Pharmacol. 2008 Oct;155(3):288-90. | |||||
| REF 69 | Synthesis and profile of SCH351591, a novel PDE4 inhibitor. Bioorg Med Chem Lett. 2002 Jun 17;12(12):1621-3. | |||||
| REF 70 | Antiasthmatic effect of YM976, a novel PDE4 inhibitor, in guinea pigs. J Pharmacol Exp Ther. 2001 Apr;297(1):165-73. | |||||
| REF 71 | Effects of a selective PDE4 inhibitor, D-22888, on human airways and eosinophils in vitro and late phase allergic pulmonary eosinophilia in guinea pigs. Pulm Pharmacol Ther. 1998 Feb;11(1):13-21. | |||||
| REF 72 | Dual inhibition of human type 4 phosphodiesterase isostates by (R, R)-(+/-)-methyl 3-acetyl-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3- methyl-1-pyrrolidinecarboxylate. Biochemistry. 1998 May 12;37(19):6894-904. | |||||
| REF 73 | Preclinical trials in Chronic obstructive pulmonary disease in Japan (PO). 2004 | |||||
| REF 74 | Substituted furans as inhibitors of the PDE4 enzyme. Bioorg Med Chem Lett. 1999 Feb 8;9(3):323-6. | |||||
| REF 75 | PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-{beta}1-stimulated fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2009 Jun;296(6):L959-69. | |||||
| REF 76 | Effects of alkyl substitutions of xanthine skeleton on bronchodilation. J Med Chem. 1992 Oct 30;35(22):4039-44. | |||||
| REF 77 | Hunting the emesis and efficacy targets of PDE4 inhibitors: identification of the photoaffinity probe 8-(3-azidophenyl)-6- [(4-iodo-1H-1-imidazolyl... J Med Chem. 2000 Oct 19;43(21):3820-3. | |||||
| REF 78 | Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phos... J Med Chem. 2000 Feb 24;43(4):675-82. | |||||
| REF 79 | Discovery of potent cyclic GMP phosphodiesterase inhibitors. 2-Pyridyl- and 2-imidazolylquinazolines possessing cyclic GMP phosphodiesterase and th... J Med Chem. 1995 Sep 1;38(18):3547-57. | |||||
| REF 80 | 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]indol... J Med Chem. 2000 Dec 14;43(25):4850-67. | |||||
| REF 81 | A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity. J Med Chem. 1985 May;28(5):537-45. | |||||
| REF 82 | Effect of orally administered KF66490, a phosphodiesterase 4 inhibitor, on dermatitis in mouse models. Int Immunopharmacol. 2009 Jan;9(1):55-62. | |||||
| REF 83 | A prenylated flavonol, sophoflavescenol: a potent and selective inhibitor of cGMP phosphodiesterase 5. Bioorg Med Chem Lett. 2002 Sep 2;12(17):2313-6. | |||||
| REF 84 | The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors. Bioorg Med Chem Lett. 2010 Sep 15;20(18):5502-5. | |||||
| REF 85 | Discovery of L-791,943: a potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor. Bioorg Med Chem Lett. 2002 Jun 3;12(11):1457-61. | |||||
| REF 86 | Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase. J Med Chem. 2006 Mar 23;49(6):1867-73. | |||||
| REF 87 | Pharmacology of a novel, orally active PDE4 inhibitor. Pharmacology. 2009;83(5):275-86. | |||||
| REF 88 | Synthesis and biological evaluation of 2,5-dihydropyrazol. Bioorg Med Chem Lett. 2000 Dec 4;10(23):2661-4. | |||||
| REF 89 | Discovery of micromolar PDE IV inhibitors that exhibit much reduced affinity for the [3H]rolipram binding site: 3-norbornyloxy-4-methoxyphenylmethylene oxindoles, Bioorg. Med. Chem. Lett. 5(17):1965-1968 (1995). | |||||
| REF 90 | Novel heterocyclic-fused pyridazinones as potent and selective phosphodiesterase IV inhibitors. J Med Chem. 1997 May 9;40(10):1417-21. | |||||
| REF 91 | Comparison of recombinant human PDE4 isoforms: interaction with substrate and inhibitors. Cell Signal. 1998 Jun;10(6):427-40. | |||||
| REF 92 | First dual M3 antagonists-PDE4 inhibitors: synthesis and SAR of 4,6-diaminopyrimidine derivatives. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1834-9. | |||||
| REF 93 | Fragment-based screening for inhibitors of PDE4A using enthalpy arrays and X-ray crystallography. J Biomol Screen. 2012 Apr;17(4):469-80. | |||||
| REF 94 | Crystal structure of human PDE4a with 4-(3-butoxy-4-methoxyphenyl)methyl-2-imidazolidone | |||||
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