Target Information

Target General Information

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Target ID

T61744 (Former ID: TTDS00280)

Target Name

Phosphodiesterase 4A (PDE4A)

Synonyms

cAMP-specific 3',5'-cyclic phosphodiesterase 4A; Type 4A cAMP phosphodiesterase; PDE46; DPDE2

Gene Name

PDE4A

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Asthma [ICD-11: CA23]

Function

Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

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BioChemical Class

Phosphoric diester hydrolase

UniProt ID

PDE4A_HUMAN

EC Number

EC 3.1.4.53

Sequence

MEPPTVPSERSLSLSLPGPREGQATLKPPPQHLWRQPRTPIRIQQRGYSDSAERAERERQ
PHRPIERADAMDTSDRPGLRTTRMSWPSSFHGTGTGSGGAGGGSSRRFEAENGPTPSPGR
SPLDSQASPGLVLHAGAATSQRRESFLYRSDSDYDMSPKTMSRNSSVTSEAHAEDLIVTP
FAQVLASLRSVRSNFSLLTNVPVPSNKRSPLGGPTPVCKATLSEETCQQLARETLEELDW
CLEQLETMQTYRSVSEMASHKFKRMLNRELTHLSEMSRSGNQVSEYISTTFLDKQNEVEI
PSPTMKEREKQQAPRPRPSQPPPPPVPHLQPMSQITGLKKLMHSNSLNNSNIPRFGVKTD
QEELLAQELENLNKWGLNIFCVSDYAGGRSLTCIMYMIFQERDLLKKFRIPVDTMVTYML
TLEDHYHADVAYHNSLHAADVLQSTHVLLATPALDAVFTDLEILAALFAAAIHDVDHPGV
SNQFLINTNSELALMYNDESVLENHHLAVGFKLLQEDNCDIFQNLSKRQRQSLRKMVIDM
VLATDMSKHMTLLADLKTMVETKKVTSSGVLLLDNYSDRIQVLRNMVHCADLSNPTKPLE
LYRQWTDRIMAEFFQQGDRERERGMEISPMCDKHTASVEKSQVGFIDYIVHPLWETWADL
VHPDAQEILDTLEDNRDWYYSAIRQSPSPPPEEESRGPGHPPLPDKFQFELTLEEEEEEE
ISMAQIPCTAQEALTAQGLSGVEEALDATIAWEASPAQESLEVMAQEASLEAELEAVYLT
QQAQSTGSAPVAPDEFSSREEFVVAVSHSSPSALALQSPLLPAWRTLSVSEHAPGLPGLP
STAAEVEAQREHQAAKRACSACAGTFGEDTSALPAPGGGGSGGDPT

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

HIT2.0 ID

T95GWW

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Dyphylline

Drug Info

Approved

Acute bronchial asthma

[2], [3], [4]

Enprofylline

Drug Info

Approved

Asthma

[5]

Clinical Trial Drug(s)

[+] 20 Clinical Trial Drugs

DENBUFYLLINE

Drug Info

Phase 3

Cognitive impairment

[6]

SOTB07

Drug Info

Phase 3

Asthma

[7]

AN-2898

Drug Info

Phase 2

Atopic dermatitis

[8]

AWD-12-281

Drug Info

Phase 2

Rhinitis

[9]

CC-1088

Drug Info

Phase 2

Crohn disease

[10]

GPD-1116

Drug Info

Phase 2

Asthma

[11]

HT-0712

Drug Info

Phase 2

Cognitive impairment

[12]

LIRIMILAST

Drug Info

Phase 2

Chronic obstructive pulmonary disease

[13]

MK-0873

Drug Info

Phase 2

Psoriasis vulgaris

[14]

Oglemilast

Drug Info

Phase 2

Asthma

[15]

OX-914

Drug Info

Phase 2

Asthma

[16]

Piclamilast

Drug Info

Phase 2

Rheumatoid arthritis

[17]

Revamilast

Drug Info

Phase 2

Asthma

[18]

TA-7906

Drug Info

Phase 2

Atopic dermatitis

[19]

TOFIMILAST

Drug Info

Phase 2

Chronic obstructive pulmonary disease

[20]

Tofisopam

Drug Info

Phase 2

Irritable bowel syndrome

[21]

AVE-8112

Drug Info

Phase 1

Parkinson disease

[22]

GSK-356278

Drug Info

Phase 1

Huntington disease

[23]

MEM-1414

Drug Info

Phase 1

Mood disorder

[24]

Ronomilast

Drug Info

Phase 1

Chronic obstructive pulmonary disease

[25]

Discontinued Drug(s)

[+] 16 Discontinued Drugs

Cilomilast

Drug Info

Discontinued in Phase 3

Chronic obstructive pulmonary disease

[26], [27]

CDP840

Drug Info

Discontinued in Phase 2

Chronic obstructive pulmonary disease

[28]

CI-1018

Drug Info

Discontinued in Phase 2

Asthma

[29]

Daxalipram

Drug Info

Discontinued in Phase 2

Multiple sclerosis

[30]

GSK256066

Drug Info

Discontinued in Phase 2

Asthma

[31]

KW-4490

Drug Info

Discontinued in Phase 2

Asthma

[32]

LAS-37779

Drug Info

Discontinued in Phase 2

Psoriasis vulgaris

[33]

V-11294A

Drug Info

Discontinued in Phase 2

Asthma

[34]

D-4418

Drug Info

Discontinued in Phase 1

Cutaneous T-cell lymphoma

[35]

SCH-351591

Drug Info

Discontinued in Phase 1

Chronic obstructive pulmonary disease

[36]

YM-976

Drug Info

Discontinued in Phase 1

Asthma

[37], [38]

D-22888

Drug Info

Terminated

Allergy

[39]

GW-3600

Drug Info

Terminated

Asthma

[40]

NIK-616

Drug Info

Terminated

Chronic obstructive pulmonary disease

[41]

TJN-598

Drug Info

Terminated

Glomerulonephritis

[42]

Torbafylline

Drug Info

Terminated

Peripheral vascular disease

[43]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 80 Inhibitor drugs

Dyphylline

Drug Info

[1]

Enprofylline

Drug Info

[5]

DENBUFYLLINE

Drug Info

[44]

SOTB07

Drug Info

[45]

AN-2898

Drug Info

[46]

AWD-12-281

Drug Info

[47]

CC-1088

Drug Info

[48]

GPD-1116

Drug Info

[11]

HT-0712

Drug Info

[45]

LIRIMILAST

Drug Info

[49]

MK-0873

Drug Info

[50]

Oglemilast

Drug Info

[49]

OX-914

Drug Info

[51]

Piclamilast

Drug Info

[52]

Revamilast

Drug Info

[53]

TA-7906

Drug Info

[54]

TOFIMILAST

Drug Info

[55]

Tofisopam

Drug Info

[56]

AVE-8112

Drug Info

[57]

GSK-356278

Drug Info

[58]

MEM-1414

Drug Info

[59]

Ronomilast

Drug Info

[60]

Cilomilast

Drug Info

[27]

CDP840

Drug Info

[61]

CI-1018

Drug Info

[62]

Daxalipram

Drug Info

[63]

GSK256066

Drug Info

[64]

KW-4490

Drug Info

[65]

LAS-37779

Drug Info

[66]

V-11294A

Drug Info

[67]

D-4418

Drug Info

[68]

SCH-351591

Drug Info

[69]

YM-976

Drug Info

[70]

D-22888

Drug Info

[71]

GW-3600

Drug Info

[72]

NIK-616

Drug Info

[73]

TJN-598

Drug Info

[42]

Torbafylline

Drug Info

[43]

(2,5-Diphenyl-furan-3-yl)-phenyl-methanone

Drug Info

[74]

(R)-Rolipram

Drug Info

[75]

(S)-Rolipram

Drug Info

[75]

1-Butyl-3-methyl-3,7-dihydro-purine-2,6-dione

Drug Info

[76]

1-Methyl-3-propyl-3,7-dihydro-purine-2,6-dione

Drug Info

[76]

2,5-Bis-(3,4-dimethoxy-phenyl)-furan

Drug Info

[74]

2,5-Bis-(3-cyclopentyloxy-4-methoxy-phenyl)-furan

Drug Info

[74]

4-(2,5-Diphenyl-furan-3-yl)-morpholine

Drug Info

[74]

6-Azido-8-(3-iodo-phenyl)-quinoline

Drug Info

[77]

6-Imidazol-1-ylmethyl-8-phenyl-quinoline

Drug Info

[77]

8-(3-Azido-phenyl)-6-iodo-quinoline

Drug Info

[77]

8-(3-Azido-phenyl)-6-pyridin-4-ylmethyl-quinoline

Drug Info

[77]

8-(3-Nitro-phenyl)-6-phenyl-[1,7]naphthyridine

Drug Info

[78]

8-(3-Nitro-phenyl)-6-pyridin-4-ylmethyl-quinoline

Drug Info

[77]

AL-59640

Drug Info

[45]

ASP-3258

Drug Info

[45]

Benzyl-(2-imidazol-1-yl-quinazolin-4-yl)-amine

Drug Info

[79]

Benzyl-(2-phenyl-quinazolin-4-yl)-amine

Drug Info

[79]

Benzyl-(2-pyridin-3-yl-quinazolin-4-yl)-amine

Drug Info

[79]

Benzyl-(2-pyridin-4-yl-quinazolin-4-yl)-amine

Drug Info

[79]

Benzyl-(2-thiophen-2-yl-quinazolin-4-yl)-amine

Drug Info

[79]

CD-160130

Drug Info

[45]

CH-3697

Drug Info

[45]

CHF-5480

Drug Info

[45]

CI-1044

Drug Info

[80]

isobutylmethylxanthine

Drug Info

[81]

KF-66490

Drug Info

[82]

KURAIDIN

Drug Info

[83]

KURARINOL

Drug Info

[83]

L-454560

Drug Info

[84]

L-791943

Drug Info

[85]

L-869298

Drug Info

[86]

NIS-62949

Drug Info

[87]

NITRAQUAZONE

Drug Info

[88]

OCID-2987

Drug Info

[45]

ROLIPRAM

Drug Info

[89]

RS-14491

Drug Info

[90]

RS-25344

Drug Info

[91]

SOPHOFLAVESCENOL

Drug Info

[83]

TAS-203

Drug Info

[45]

UCB-101333-3

Drug Info

[92]

ZL-N-91

Drug Info

[45]

Chemical Structure based Activity Landscape of Target

Top

Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

Top

Target-regulating microRNAs

Target-regulating microRNAs Info

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 3 KEGG Pathways

Purine metabolism

cAMP signaling pathway

Morphine addiction

Reactome

[+] 2 Reactome Pathways

DARPP-32 events

G alpha (s) signalling events

WikiPathways

[+] 1 WikiPathways

G Protein Signaling Pathways

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

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

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

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

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

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