Phosphodiesterase-4 inhibitors: A review of current developments (2010-2012)

Expert Opinion on Therapeutic Patents

Volumn 23, Issue 8, 2013, Pages 997-1016

  Gavaldà, Amadeu ^a   Roberts, Richard S ^a  

^a Department of Integrative Pharmacology ^*  (Spain)

Author keywords

Asthma; Atopic dermatitis; Chronic obstructive pulmonary disease; Dual activity; Emesis; Inhalation; PDE4; Psoriasis; Respiratory disease; Rheumatoid arthritis; Topical

Indexed keywords

AN 2728; AN 2898; APREMILAST; DE 103; E 6005; ELBIMILAST; GAMMA INTERFERON; GSK 256066; INTERLEUKIN 10; INTERLEUKIN 12; MEM 1414; METHOTREXATE; OGLEMILAST; PHOSPHODIESTERASE IV INHIBITOR; PLACEBO; REVAMILAST; ROFLUMILAST; RPL 554; SALBUTAMOL; TETOMILAST; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ALLERGIC CONJUNCTIVITIS; ALLERGIC RHINITIS; ANKYLOSING SPONDYLITIS; ANTIINFLAMMATORY ACTIVITY; AREA UNDER THE CURVE; ASTHMA; ATOPIC DERMATITIS; AUTOIMMUNE DISEASE; BEHCET DISEASE; BRONCHODILATATION; CHRONIC OBSTRUCTIVE LUNG DISEASE; CYTOKINE PRODUCTION; DISEASE ACTIVITY; DOSAGE SCHEDULE COMPARISON; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG INDUSTRY; DRUG SAFETY; DRUG SOLUBILITY; DRUG TOLERABILITY; DRUG WITHDRAWAL; EX VIVO STUDY; FORCED EXPIRATORY VOLUME; HEADACHE; HEART MUSCLE ISCHEMIA; HIGH THROUGHPUT SCREENING; HUMAN; IC 50; LIMIT OF QUANTITATION; LUNG FUNCTION; LUNG INJURY; MAXIMUM PLASMA CONCENTRATION; MONOTHERAPY; NAUSEA; NAUSEA AND VOMITING; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PNEUMONIA; PSORIASIS; PSORIASIS VULGARIS; PSORIATIC ARTHRITIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REPERFUSION INJURY; REVIEW; RHEUMATOID ARTHRITIS; RHINITIS; SEPSIS; SINGLE DRUG DOSE; STATISTICAL SIGNIFICANCE; TREATMENT RESPONSE; ULCERATIVE COLITIS; UNSPECIFIED SIDE EFFECT;

ADMINISTRATION, ORAL; AMINOPYRIDINES; ANIMALS; BENZAMIDES; CYCLOPROPANES; DRUG APPROVAL; DRUG DELIVERY SYSTEMS; DRUG DESIGN; DRUG INDUSTRY; HUMANS; PATENTS AS TOPIC; PHOSPHODIESTERASE 4 INHIBITORS; THALIDOMIDE;

EID: 84880662137     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2013.794789     Document Type: Review

References (153)

1. Conti M, Beavo J Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signalling Ann Rev Biochem 2007;76:481-511
2. Bingham J, Sudarsanam S, Srinivasan S Profiling human phosphodiesterase genes and splice isoforms Biochem Biophys Res Commun 2006;350:25-32
3. Houslay MD Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown Trends Biochem Sci 2010;35:91-100
4. Houslay MD, Schafer P, Zhang KY Keynote review: phosphodiesterase-4 as a therapeutic target Drug Discov Today 2005;10:1503-19
5. Press NJ, Banner KH PDE4 inhibitors-A review of the current field Prog Med Chem 2009;47:37-74
6. O'Donnell JM, Zhang HT Antidepressant effects of inhibitors of cyclic AMP phosphodiesterase (PDE4) Trends Pharmacol Sci 2004;25:158-63
7. Robichaud A, Stamatiou PB, Jin S-L, et al Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptormediated anesthesia, a behavioral correlate of emesis J Clin Invest 2002;110:1045-52
8. Li YF, Cheng YF, Huang Y, et al Phosphodiesterase-4D knockout and RNAi-mediated knockdown enhance memory and increase hippocampal neurogenesis via increased cAMP signaling J Neurosci 2011;31:172-83
9. Zhang HT Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs Curr Pharm Des 2009;15:1688-98
10. Wang H, Peng MS, Chen Y, et al Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors Biochem J 2007;408:193-201
11. Jin SL, Conti M Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNFa responses Proc Natl Acad Sci USA 2002;99:7628-33
12. Manning CD, Burman M, Christensen SB, et al Suppression of human inflammatory cell function by subtype-selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B Br J Pharmacol 1999;128:1393-8
13. Lehnart SE, Wehrens XH, Reiken S, et al Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias Cell 2005;123:25-35
14. Robichaud A, Stamatiou PB, Jin SL, et al Deletion of phosphodiesterase 4D in mice shortens a2-adrenoceptor-mediated anaesthesia, a behavioural correlate of emesis J Clin Invest 2002;110:1045-52
15. Mori F, Perez-Torres S, De Caro R, et al The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D J Chem Neuroanat 2010;40:36-42
16. Summary of the European public assessment report (EPAR) for Daxas Avaialble from http://www.ema.europa eu/ema/index.jsp?curl=pages/medicines/ human/medicines/001179/human-med-001363 jsp&mid=WC0b01ac058001d124 [Last accessed 15 January 2013]
17. FDA News release 2011 Avaialble from http://www.fda gov/NewsEvents/ newsroom/PressAnnouncements/ucm244989.htm [Last accessed 15 January 2013]
18. GOLD Global strategy for the diagnosis, management and prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 Available from: http://www.goldcopd.org [Last accessed 15 January 2013]
19. Rennard SI, Calverley PM, Goehring UM, et al Reduction of exacerbations by the PDE4 inhibitor Roflumilast-The importance of defining different subsets of patients with COPD Respir Res 2011;12:18
20. Clinical trials for Roflumilast Avaialble from http://www.clinicaltrials. gov/ct2/results?term=roflumilast [Last accessed 15 January 2013]
21. Pages L, Gavalda A, Lehner MD PDE4 inhibitors: a review of current developments (2005-2009) Expert Opin Ther Pat 2009;19:1501-19
22. Schafer PH, Parton A, Gandhi AK, et al Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis Br J Pharmacol 2010;159:842-55
23. Celgene product pipeline Avaialble from http://www.celgene.com/pdfs/ product-pipeline.pdf [Last accessed 15 January 2013]
24. Papp K, Cather JC, Rosoph L, et al Efficacy of Apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial Lancet 2012;380:738-46
25. Positive phase IIb topline clinical data for celgene oral compound apremilast (CC-10004) reported for patients with moderate-to-severe Avaialble from http://ir.celgene.com/phoenix.zhtml? c=111960&p=irol-newsArticle& ID=1365878&highlight=apremilast [Last accessed 15 January 2013]
26. Phase II study evaluating apremilast as an oral treatment for patients with Ankylosing Spondylitis Presented at ACR Avaialble from http://ir.celgene com/phoenix.zhtml?c=111960&p=irolnewsArticle& ID=1627508&highlight= apremilast [Last accessed 15 January 2013]
27. Oral apremilast achieves statistical significance for the primary endpoint of ACR20 in the first phase III study (PALACE-1) in patients with psoriatic arthritis Avaialble from http://ir.celgene com/phoenix.zhtml?c= 111960&p=irolnewsArticle- print&ID=1758233& highlight= [Last accessed 15 January 2013]
28. Apremilast ESTEEM program meets primary and major secondary endpoint in pivotal phase III psoriasis trials Avaialble from http://ir.celgene.com/phoenix. zhtml?c=111960&p=irolnewsArticle& ID=1771804&highlight= [Last accessed 15 January 2013]
29. Clinical trials for Apremilast Avaialble from http://www.clinicaltrials. gov/ct2/results?term=apremilast&pg=1 [Last accessed 15 January 2013]
30. Lotvall J, Lundback B Phosphodiesterase inhibitors in obstructive lung disease In: Lotvall J, editor Advances in combination therapy for asthma and COPD John Wiley and Sons, Hoboken, NJ; 2012
31. Glenmark initiates phase IIb human trials globally for its novel Molecule Revamilast Avaialble from http://wwwglenmarkpharma.com/GLN-NWS/PDF/Revamilast- PhII-initiated.pdf [Last accessed 15 January 2013]
32. Clinical trials for Revamilast Avaialble from http://clinicaltrials.gov/ ct2/results? term=Revamilast [Last accessed 15 January 2013]
33. A Clinical Trial to Study the Effects of Revamilast in Patients With Rheumatoid Arthritis (TERRA) Avaialble from http://clinicaltrials.gov/ct2/show/ NCT01430507? term=Revamilast&rank=1 [Last accessed 15 January 2013]
34. A clinical trial to study the effects of revamilast in patients with chronic persistent asthma Avaialble from http://clinicaltrials.gov/ct2/show/ NCT01436890? term=Revamilast&rank=2 [Last accessed 15 January 2013]
35. Santen Pharmaceutical Co, Ltd Annual Report 2009 Avaialble from http://wwwsanten.com/ir/events/mtg2009-3q.pdf [Last accessed 15 January 2013]
36. Shakur Y, Hensley J, Kambayashi J Tetomilast (OPC-6535): Inhibition of human T-cell proliferation and cytokine release [abstract MON-G-135] 14th United Eur Gastroenterol Week (UEGW); 21-25 October 2006; Berlin
37. Ichikawa H, Okamoto S, Kamada N, et al Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL-10-deficient mice Inflamm Bowel Dis 2008;11:1483-90
38. Hasegawa T, Sakurai K, Kambayashi Y, et al Effects of OPC-6535 on lipopolysaccharide-induced acute liver injury in the rat: involvement of superoxide and tumor necrosis factor-alpha from hepatic macrophages Surgery 2003;134:818-26
39. Nagamoto H, Maeda T, Haruta JP, et al OPC-6535, a novel oral thiazole compound, supresses colonic damage in a rat model of T-induced colitis Gastroenterology 2004;126(Suppl2):M1044
40. Bloomfield GL, Ridings PC, Blocher CR, et al OPC-6535, a superoxide anion production inhibitor, attenuates acute lung injury J Surg Res 1997;72:70-7
41. Onogawa T, Nagamoto H, Maeda T, et al The protective effect of an inhibitor of leukocyte activation (OPC-6535) on myocardial reperfusion injury in a pig model J Mol Cell Cardiol 1998;30:A37
42. Bickston SJ, Snider KR, Kappus MR Tetomilast: new promise for phosphodiesterase-4 inhibitors? Expert Opin Investig Drugs 2012;21:1845-9
43. Mallikaarjun S, Shoaf S, Zhang P, et al Pharmacokinetics (PK) and pharmacodynamics (PD) of Tetomilast in stable COPD subjects [abstract No P3838] European Respiratory Society (ERS) 2006 Congress; Munich, Germany; 2006
44. Wise RA, Littner MR, Zhang P, et al Clinical evaluation of a new inhibitor of neutrophilic inflammation, Tetomilast (OPC-6535) in chronic obstructive pulmonary disease [abstract No P3052] European Respiratory Society (ERS) 2006 Congress; Munich, Germany; 2006
45. Clinical trials for Tetomilast Available from: http://www.clinicaltrials. gov/ct2/results?term=tetomilast [Last accessed 15 January 2013]
46. Leaker BR, Singh D, Barnes PJ, et al The effect of the novel phosphodiesterase-4 inhibitor MEM 1414 on the allergen-induced responses in mild asthma [Poster Board: J18, Publication Page: A5613] American Thoracic Society International Conference; 14-19 May2010; New Orleans
47. Roche pharmaceuticals pipeline Available from: http://www.roche.com/ research-and-development/pipeline/roche-pharma-pipeline.htm [Last accessed 15 January 2013]
48. Kuss H, Egerland U, Hoefgen N, et al The in vivo activity of AWD 12-353, a potent phosphodiesterase 4 (PDE4) inhibitor for the treatment of allergic asthma and COPD Eur Resp J 2003;22(Suppl 45):P742
49. Piggott C Ronomilast (ELB353, PDE4 inhibitor), Euro-Biotech Forum Paris, 2010
50. Biotie Product and development Available from: http://www.biotie.com/en/ product-and-development/inflammation/ronomilast [Last accessed 15 January 2013]
51. Bloomberg press release Available from: http://www.bloomberg.com/news/ 2013-01-21/biotie-considers-developingalzheimer-s-drug-on-its-own.html? cmpid=yhoo [Last accessed 31 January 2013]
52. Tralau-Stewart CJ, Williamson RA, Nials AT, et al 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;337:145-54
53. Singh D, Petavy F, Macdonald AJ, et al The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma Respir Res 2010;11:26
54. GSK product pipeline Available from: http://www.gsk.com/investors/ productpipeline html [Last accessed 17 January 2013]
55. A single dose of RPL554 is safe and effective in patients with asthma 2009 Available from: http://wwwveronapharma.com/joomla/news/projectnews/2009/ 163-a-single-dose-of-rpl554-is-safe-and-effective-in-patients-withasthma [Last accessed 15 January 2013]
56. Verona Pharma announces positive results for RPL554 in mild asthma at higher doses 2011 Available from: http://wwwveronapharma.com/joomla/images/ Documents/News/2011-02-22-NRa.pdf [Last accessed 15 January 2013]
57. Bronchodilation in asthmatics maintained with daily dosing of RPL554 2011 Available from: http://wwwveronapharma.com/joomla/images/Documents/News/2011- 08-17-NR.pdf [Last accessed 15 January 2013]
58. Verona Pharma reports bronchodilator data with RPL554 in COPD patients at the 2012 European Respiratory Society 2012 Available from: http:// wwwveronapharma.com/joomla/images/Documents/News/2012-09-04-NR.pdf [Last accessed 15 January 2013]
59. Zane LT, Toledo-Bahena M, Hughes MH, et al Safety and Efficacy of AN2728 Ointment in a Phase 2b Dose-Ranging, Bilateral Study of Mild-to-Moderate Plaque Psoriasis 71st Society of Investigative Dermatology (SID) meeting; 4-7 May 2011; Phoenix, Arizona
60. Toledo-Bahena M, Zane LT Safety and efficacy of AN2728 ointment in a 12-week, randomized, double-blind, vehicle-controlled, bilateral trial for the treatment of psoriasis 41st European Society for Dermatological Research (ESDR); 7-10 Sept 2011; Barcelona, Spain
61. Zane LT, Gogoleva T, Heerinckx FA, et al Safety and efficacy of AN2728 and AN2898 ointments in a phase 2a bilateral study of mild-to-moderate atopic dermatitis 72nd Society of Investigative Dermatology (SID)Raleigh; 9-12 May 2012; North Carolina
62. Anacor pipeline AN2728 Available from: http://www.anacor.com/an2728 php [Last accessed 15 January 2013]
63. Sanders V, Rock F, Kimura R, et al AN2898, a novel oxaborole compound with anti-inflammatory activity: mechanism of action and in vitro cytokine inhibition International Investigative Dermatology Conference, 14-18 May 2008; Kyoto, Japan
64. Maples K, Bu W, Liu L, et al AN2898, a novel oxaborole compound with anti-inflammatory activity: results of in vivo efficacy and preclinical safety studies International Investigative Dermatology Conference; 14-18 May 2008; Kyoto, Japan
65. Eisai 2012 Major R&D pipeline Available from: www.eisai.com/pdf/eir/ erepo/epipeline.pdf [Last accessed 15 January 2013]
66. Card GL, England BP, Suzuki Y, et al structural basis for the activity of drugs that inhibit phosphodiesterases Structure 2004;12:2233-47
67. Auspex Pharmaceuticals Inc Pyrrolidinone inhibitors of PDE-4 US20100159034; 2010
68. Celgene Corporation Isotopologues of isoindole derivatives WO2012097116; 2012
69. Concert Pharmaceuticals Inc Deuterated isoindoline-1,3-dione derivatives as PDE4 and THF-alpha inhibitors WO2010147922; 2010
70. Concert Pharmaceuticals Inc KR2012071261; 2012
71. Celgene Corporation Phenethylsulfone isoindoline derivatives and their use US20120178708; 2012
72. Tianjin Hemay Biotech Co Ltd Thiophene derivatives WO2010130224; 2010
73. Nektar Therapeutics Oligomer-containing apremilast moiety compounds WO2012083153; 2012
74. Chiesi Farmaceutici SPA Ester derivatives as phosphodiesterase inhibitors WO2009077068; 2009; Chiesi Farmaceutici SPA EP2070913; 2009
75. Chiesi Farmaceutici SPA Phosphodiesterase-4 inhibitors belonging to the tertiary amine class US20090258905; 2009
76. Chiesi Farmaceutici SPA Benzoic acid (1-phenyl-2-pyridin-4-yl)ethyl esters as phosphodiesterase inhibitors WO2010089107; 2010; Chiesi Farmaceutici SPA EP2216327; 2010
77. Chiesi Farmaceutici SPA Pharmaceutical formulation comprising a phosphodiesterase inhibitor WO2012016845; 2012
78. Chiesi Farmaceutici SPA Dry powder formulation comprising aphosphodiesterase inhibitor WO2012016889; 2012
79. Chiesi Farmaceutici SPA Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors WO2012168226; 2012
80. Leo Pharma AS Biaryl phosphodiesterase inhibitors WO2011134468; 2011
81. LeoPharma AS Benzodioxole or benzodioxepine heterocyclic compounds phosphodiesterase inhibitors WO2011160632; 2011
82. Kalypsys Inc Heteroarylalkoxysubstituted quinolone inhibitors of PDE4 WO2011093924; 2011; Kalypsys Inc US20100081646; 2010
83. Via Pharmaceuticals Inc 5-Substituted-1,4-benzodiazepines as phosphodiesterase inhibitors WO2009037302; 2009
84. Nycomed GMBH Novel pyrazolonederivatives and their use as PD4 inhibitors WO2010055083; 2010
85. Mitsubishi Tanabe Pharma Corp Ointment with excellent formulation stability WO2012133492; 2012
86. Helicon Therapeutics Inc Therapeutic piperazines WO2012040258; 2012; Helicon Therapeutics Inc US20110065691; 2011
87. Memory Pharmaceuticals Corp Phosphodiesterase 4 inhibitors WO2010003084; 2010
88. H L Hall & Sons Ltd Use of pharmaceutical compositions containing mesembrenone WO2010106494; 2010
89. H L Hall & Sons Ltd Sceletium extract and uses thereof WO2010106495; 2010
90. Taipei Medical University Pharmaceutical composition containing flavinoids US20090036518; 2009
91. The United States of America, as represented by the Secretary, Department of Health and Human Services Phosphodiesterase inhibitors WO2009089027; 2009
92. Korea Research Institute of Chemical Technology, S Korea KR2009058752; 2009
93. People's Republic of China CN102716110; 2012
94. -4 Aza IP NV Pyrido(3,2-d)pyrimidines and pharmaceutical compositions useful for medical treatment WO2009003669; 2009
95. Council of Scientific & Industrial Research Triazine-aryl-bis-indoles and process for preparation thereof WO2011092547; 2011
96. Leo Pharma AS Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases WO2010069322; 2010
97. Kyorin Pharmaceutical Co Ltd Heterocyclic biaryl derivative, and PDE4 inhibitor comprising same as active ingredient WO2010035745; 2010
98. Matrix Laboratories Ltd Novel heterocyclic compounds, pharmaceutical compositions containing them and processes for their preparation WO2009115874; 2009
99. Matrix Laboratories Ltd Novel PDE inhibitors, pharmaceutical compositions containing them and processes for their preparation WO2009147476; 2009
100. Nuada Inc Method for treatment of bronchial asthma US20120202868; 2012
101. Orchid Research Laboratories Ltd Heterocyclic compounds as phosphodiesterase inhibitors WO2010084402; 2010; Orchid Research Laboratories Ltd US2011269753; 2011
102. High Point Pharmaceuticals LLC Tricyclic compounds as modulators of TNF-A synthesis and as PDE4 inhibitors WO2009094528; 2009
103. Almirall SA (3-Oxo)pyridazin-4-ylurea derivatives as PDE4 inhibitors WO2010069504; 2010; Almirall SA EP2196465; 2010
104. Almirall SA 3-(5-Amino-6-oxo-1,6-dihydropyridazin-3-yl)-biphenyl derivatives as PDE4 inhibitors EP2394998; 2011
105. Almirall SA New tetrahydropyrazolo [3,4-c]isoquinolin-5-amine derivatives WO2010097172; 2010; EP2226323; 2010
106. Almirall SA New 7,8-dihydro-1,6-naphthyridin-5(6h)-one-derivatives as PDE4 inhibitors EP2380890; 2011
107. Astellas Pharma Inc Imidazo[1,2-a] pyridine derivative WO2011136192; 2011
108. Anacor Pharmaceuticals Inc Boron-containing small molecules WO2009111676; 2009
109. Anacor Pharmaceuticals Inc Boron-containing small molecules WO2010027975; 2010
110. Anacor Pharmaceuticals Inc Boron-containing small molecules WO2010028005; 2010
111. AstraZeneca AB Phenoxypyridinylamide derivatives and their use in the treatment of PDE4 mediated disease states WO2009144494; 2009
112. AstraZeneca AB Combination comprising 6-fluoro-N-((1S,4S)-4-(6-fluoro-2, 4-dioxo-1-(4'-(piperazin-1-ylmethyl) biphenyl-3-yl)-1,2-dihydropyrido [2,3-d]pyrimidin-3(4H)-yl)cyclohexyl) imidazo[1,2-a]pyridine-2-carboxamide or a salt WO2010004319; 2010
113. DeCode Genetics EHF Substituted benzoazole PDE4 inhibitors for treating pulmonary and cardiovascular disorders US20090130076; 2009
114. DeCode Genetics EHF 4-(or 5-) substituted catechol derivatives US20090131530; 2009
115. DeCode Genetics EHF Biaryl PDE4 inhibitors for treating inflammation WO2009067600; 2009
116. DeCode Genetics EHF Biaryl PDE4 inhibitors for treating pulmonary and cardiovascular disorders WO2009067621; 2009
117. DeCode Genetics EHF Substituted aza-bridged bicyclics for cardiovascular and CNS disease WO2010059836; 2010
118. DeCode Genetics EHF PDE4 inhibitors selective for the long form of PDE4 for treating inflammation and avoiding side effects WO2010059838; 2010
119. Burgin AB, Magnusson OT, Singh J, et al Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety Nat Biotech 2010;28:63-72120 People's Republic of China CN102603676; 2012
120. Orchid Research Laboratories Ltd Novel heterocycles WO2009095773; 2009
121. Gilead Sciences Inc Bi-functional pyrazolopyridine compounds US20110275622; 2011
122. Gilead Sciences Inc Bi-functional pyrazolopyridine compounds US20110275623; 2011
123. Glaxo Group Ltd Dual pharmacophores-PDE4-muscarinic antagonistics WO2009100166; 2009
124. Glaxo Group Ltd Dual pharmacophores-PDE4-muscarinic antagonistics WO2009100167; 2009
125. Glaxo Group Ltd Dual pharmacophores-PDE4-muscarinic antagonistics US20090197871; 2009
126. Glaxo Group Ltd Dual pharmacophores-PDE4-muscarinic antagonistics WO2009100169; 2009
127. Glaxo Group Ltd Dual pharmacophores-PDE4-muscarinic antagonistics WO2009100170; 2009
128. Human Biomolecular Research Institute Modulators of central nervous system neurotransmitters WO2006025920; 2006
129. Cashman JR, Voelker T, Zhang H-T, et al Dual inhibitors of phosphodiesterase-4 and serotonin re-uptake J Med Chem 2009;52:1530-9
130. Kyorin Seiyaku KK JP2010013354; 2010
131. Nycomed GMBH 3,4,4a, 10b-Tetrahydro-1H-thiopyrano-[4,3-c] isoquinoline derivatives WO2011073231; 2011
132. Biolipox AB Pyrimidinone derivaties for use as medicaments WO2010029299; 2010
133. Biolipox AB Pyrimidinones for use as medicaments WO2011114103; 2011
134. Biolipox AB Isochromenones useful in the treatment of inflammation WO2010076564; 2010
135. Ranbaxy Laboratorios Ltd Phosphodiesterase inhibitors WO2010046791; 2010
136. Trustees Boston College Inhibitors of cyclic AMP phosphodiesterases US20100227853; 2010
137. Gaeta FCA, Ledeboer A, Gross MI, Johnson KW Substituted pyrazolo[1,5-a] pyridine compounds having multi-target activity WO2010144416; 2010
138. Basilea Pharmaceutica AG Macrolides for treating diseases mediated through PDE inhibition WO2009098320; 2009
139. Basilea Pharmaceutica AG New macrolides and their use WO2009106419; 2009
140. Basilea Pharmaceutica AG New macrolides and their use WO2011018510; 2011
141. Joshi T, Hill SM, Tannheimer S, et al GS-5759, a novel Bi-functional Phosphodiesterase 4 Inhibitor and Long-Acting Beta2-Adrenoreceptor Agonist, augments GRE-dependent transcription in Human airway epithelial cells American Thoracic Society International Conference; 18-23 May 2012 p E22
142. Gentzler TT, Cui ZH, Hartsough KC, et al GS-5759, a novel Bi-functional Phosphodiesterase 4 Inhibitor and Long-Acting Beta2-Adrenoreceptor Agonist Is Efficacious in Rodent Models of Pulmonary Inflammation and Does not cause emesis in Ferrets American Thoracic Society International Conference; 18-23 May 2012 p E25
143. McDonald J, Doyle-Eisele M, Rudolph K, et al GS-5759, a novel Bi-functional Phosphodiesterase 4 Inhibitor and Long-Acting Beta2-Adrenoreceptor Agonist: Evaluation of its Bronchodilator and Anti-inflammatory Pharmacology in Non-human Primates American Thoracic Society International Conference; 18-23 May 2012 p E27
144. Cui Z, Gentzler TT, Wright CD, et al GS-5759, a novel Bi-functional phosphodiesterase 4 inhibitor and long-acting beta2-adrenoreceptor agonist, in vivo characterization of the bronchodilator pharmacology and safety in guinea pigs American Thoracic Society International Conference; 18-23 May 2012 p J4
145. Xu RX, Hassell AM, Vanderwall D, et al Atomic Structure of PDE4: Insights into phosphodiesterase mechanism and specificity Science 2000;288:1822-5
146. Huai Q, Colicelli J, Ke H The crystal structure of AMP-Bound PDE4 suggests a mechanism for phosphodiesterase catalysis Biochemistry 2003;42:13220-6
147. Wang H, Robinson H, Ke H The molecular basis for different recognition of substrates by phosphodiesterase families 4 and 10 J Mol Biol 2007;371:302-7
148. Huai Q, Sun Y, Wang H, et al enantiomer discrimination illustrated by the high resolution crystal structure of type 4 phosphodiesterase J Med Chem 2006;49:1867-73
149. Hamblin JN, Angell TDR, Ballantine SP, et al Pyrazolopyridines as a novel structural class of potent and selective PDE4 inhibitors Bioorg Med Chem Lett 2008;18:4237-41
150. Lunniss CJ, Cooper AWJ, Eldred CD, et al Quinolines as a novel structural class of potent and selective PDE4 inhibitors Optimisation for oral administration Bioorg Med Chem Lett 2009;19:1380-5
151. Woodrow MD, Ballantine SP, Barker MD Quinolines as a novel structural class of potent and selective PDE4 inhibitors Optimisation for inhaled administration Bioorg Med Chem Lett 2009;19:5261-5
152. Govek SP, Oshiro G, Anzola JV, et al Water-soluble PDE4 inhibitors for the treatment of dry eye Bioorg Med Chem Lett 2010;20:2928-32
153. Nankervis JL, Feil SC, Hancock NC, et al Thiophene inhibitors of PDE4: Crystal structures show a second binding mode at the catalytic domain of PDE4D2 Bioorg Med Chem Lett 2011;21:7089-93