Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: Advances in the development of specific phosphodiesterase inhibitors

Medicinal Research Reviews

Volumn 25, Issue 2, 2005, Pages 229-244

  Castro, Ana ^a,c,d,e   Jerez, Maria Jose ^a,f,g   Gil, Carmen ^a,f   Martinez, Ana ^a,b,f  

^a INSTITUTO DE QUÍMICA MÉDICA   (Spain)

^b Neuropharma SA   (Spain)

^c UNIVERSIDAD AUTÓNOMA DE MADRID   (Spain)

^d UNIVERSITY OF OXFORD   (United Kingdom)

^e Medicinal Chemistry Institute   (Spain)

^f UNIVERSIDAD COMPLUTENSE DE MADRID   (Spain)

^g INSTITUTO DE SALUD CARLOS III   (Spain)

Author keywords

c AMP; Immune system; Inflammatory system; Phosphodiesterase inhibitors; T cell

Indexed keywords

2 [4 [6,7 DIETHOXY 2,3 BIS(HYDROXYMETHYL) 1 NAPHTHYL] 2 PYRIDYL] 4 (3 PYRIDYL) 1(2H) PHTHALAZINONE; 4 [6,7 DIETHOXY 2,3 BIS(HYDROXYMETHYL) 1 NAPHTHYL] 1 (2 METHOXYETHYL) 2(1H) PYRIDINONE; 8 BROMOGUANINE; 9 (2 FLUOROBENZYL) 6 N METHYL 2 TRIFLUOROMETHYLADENINE; CL 1044; CYCLIC AMP; CYCLIC GMP; CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; GUANINE DERIVATIVE; IBUDILAST; IMMUNOMODULATING AGENT; INTERLEUKIN 12; INTERLEUKIN 1BETA; INTERLEUKIN 6; INTERLEUKIN 8; ISOBUTYLMETHYLXANTHINE; ISOQUINOLINE DERIVATIVE; L 791 943; L 826 141; MESOPRAM; N ADAMANTANYLTETRAHYDROPHTHALAZINONE; PENTOXIFYLLINE; PHOSPHODIESTERASE III; PHOSPHODIESTERASE INHIBITOR; PHOSPHODIESTERASE IV; PHOSPHODIESTERASE IV INHIBITOR; PHOSPHODIESTERASE VII; PHOSPHODIESTERASE VII INHIBITOR; PICLAMILAST; ROFLUMILAST; ROLIPRAM; THIADIAZOLE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; UNINDEXED DRUG; ZARDAVERINE;

AUTOIMMUNITY; CARDIOTOXICITY; DRUG BINDING SITE; DRUG SELECTIVITY; DRUG SPECIFICITY; ENZYME ACTIVITY; HUMAN; HYDROLYSIS; IMMUNE RESPONSE; IMMUNOMODULATION; IMMUNOREGULATION; MOUSE; NONHUMAN; REVIEW; SIDE EFFECT; STRUCTURE ACTIVITY RELATION; VOMITING;

3',5'-CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; ANIMALS; AUTOIMMUNE DISEASES; CYCLIC AMP; ENZYME INHIBITORS; HUMANS; IMMUNE SYSTEM; INFLAMMATION; ISOENZYMES; MODELS, CHEMICAL; PHOSPHODIESTERASE INHIBITORS; PHOSPHORIC DIESTER HYDROLASES; ROLIPRAM;

EID: 14544272401     PISSN: 01986325     EISSN: None     Source Type: Journal    
DOI: 10.1002/med.20020     Document Type: Review

References (105)

1. Conti M, Jin SL. The molecular biology of cyclic nucleotide phosphodiesterases. Prog Nucleic Acid Res Mol Biol 1999;63:1-38.
2. Vig M, George A, Sen R, Durdik J, Rath S, Bal V. Commitment of activated T cells to secondary responsiveness is enhanced by signals mediated by cAMP-dependent protein kinase A-I. Mol Pharmacol 2002;62(6):1471-1481.
3. Bevao A, Brunton LL. Cyclic nucleotide research-still expanding after half a century. Nat Rev 2002;3:710-718.
4. Antoni FA. Molecular diversity of cyclic AMP signalling. Front Neuroendocrinol 2000;21:103-132.
5. Ritcher W. 3′,5′-Cyclic nucleotide phosphodiesterases class III: Members, structure, and catalitic mechanism. Proteins 2002;46:278-286.
6. Renau TE. The potential of phosphodiesterase 4 inhibitors for the treatment of depression: Opportunities and challenges. Curr Opin Investig Drugs 2004;5(1):34-39.
7. Maurice DH, Palmer D, Tilley DG, Dunkerley HA, Netherton SJ, Raymond DR, Elbatarny HS, Jimmo SL. Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system. Mol Pharmacol 2003;64(3):533-546.
8. Burnouf C, Pruniaux MP. Recent advances in PDE4 inhibitors as immunoregulators and anti-inflammatory drugs. Curr Pharm Des 2002;8(14):1255-1296.
9. Pyne NJ, Furman BL. Cyclic nucleotide phosphodiesterases in pancreatic islets. Diabetologia 2003;46(9):1179-1189.
10. Soderling SH, Beavo JA. Regulation of cAMP and cGMP signalling: New phosphodiesterases and new functions. Current Opinion Cell Biol 2000;12:174-179.
11. Arp J, Kirchhof MG, Baroja ML, Nazarian SH, Chau TA, Strathdee CA, Ball EH, Madrenas J. Regulation of T-cell activation by phosphodiesterase 4B2 requires its dynamic redistribution during immunological synapse formation. Mol Cell Biol 2003;23(22):8042-8057.
12. Venter JC, et al. The sequence of the human genome. Science 2001;291:1304-1351.
13. Loughney K, Snyder PB, Uher L, Rosman GJ, Ferguson K, Florio VA. Isolation and characterization of PDE10A, a novel human 3′, 5′-cyclic nucleotide phosphodiesterase. Gene 1999;234(1):109-117.
14. Fawcett L, Baxendale R, Stacey P, McGrouther C, Harrow I, Soderling S, Hetman J, Beavo JA, Phillips SC. Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. Proc Natl Acad Sci USA 2000;97(7):3702-3707.
15. Soderling SH, Beavo JA. Regulation of cAMP and cGMP signaling: New phosphodiesterases and new functions. Curr Opin Cell Biol 2000;12(2):174-179.
16. Francis SH, Turko IV, Corbin JD. Cyclic nucleotide phosphodiesterases: Relating structure and function. Prog Nucleic Acid Res Mol Biol 2001;65:1-52.
17. Durinovic-Bello I, Maisel N, Schlosser M, Kaibacher H, Deeg M, Eiermann T, Karges W, Boehm BO. Relationship between T and B cell responses to proinsulin in human type 1 diabetes. Ann NY Acad Sci 2003;1005:288-294.
18. Arp J, Ozegbe P, Foey AD, Ahmed S, Williams RO. Impact of cAMP on the T-cell response to type II collagen. Immunology 2004;111(1):35-40.
19. Haraguchi S, Good RA, Day NK. Immunosuppressive retroviral peptides: cAMP and cytokine patterns. Immunol Today 1995;16(12):595-603.
20. Allison AC. Immunosuppressive drugs: The first 50 years and a glance forward. Immunopharmacology 2000;47:63-83.
21. Essayan DM. Cyclic nucleotide phosphodiesterase inhibitors and immunomodulation. Biochem Pharmacol 1999;57:965-973.
22. Dyke HJ, Montana JG. Update on the therapeutic potential of PDE4 inhibitors. Expert Opin Investig Drugs 2002;11(1):1-13.
23. Spina D. Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease. Drugs 2003;63(23):2575-2594.
24. O'Donnell JM, Zhang HT. Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci 2004;25(3):158-163.
25. Birk S, Edvinsson L, Olesen J, Kruuse C. Analysis of the effects of phosphodiesterase type 3 and 4 inhibitors in cerebral arteries. Eur J Pharmacol 2004;489(1-2):93-100.
26. Perez-Torres S, Cortes R, Tolnay M, Probst A, Palacios JM, Mengod G. Alterations on phosphodiesterase type 7 and 8 isozyme mRNA expression in Alzheimer's disease brains examined by in situ hybridization. Exp Neurol 2003;182(2):322-334.
27. Ekholm D, Hemmer B, Gao G, Vergelli M, Martin R, Manganiello V. Differential expression of cyclic nucleotide phosphodiesterase 3 and 4 activities in human T cell clones specific for myelin basic protein. J Immunol 1997;159:1520-1529.
28. Erdogan S, Houslay MD. Challenge of human Jurkat T-cells with the adenylate cyclase activator forskolin elicits major changes in cAMP phosphodiesterase (PDE) expression by up-regulating PDE3 and inducing PDE4D1 and PDE4D2 splice variants as well as down-regulating a novel PDE4A splice variant. Biochem J 1997;321:165-175.
29. Giembycz MA, Corrigan CJ, Seybold J, Newton R, Barnes PJ. Identification of cyclic AMP phosphodiesterases 3, 4 and 7 in human CD4+ and CD8+ T-lymphocytes: Role in regulating proliferation and the biosynthesis of interleukin-2. Br J Pharmacol 1996;118:1945-1958.
30. Manning CD, Burman M, Christensen SB, Cieslinski LB, Essayan DM, Grous M, Torphy TJ, Barnette MS. Suppression of human inflammatory cell function by subtype-selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B. Br J Pharmacol 1999;128(7):1393-1398.
31. Kaminuma O, Mori A, Suko M, Kikkawa H, Ikezawa K, Okudaira H. Interleukin-5 production by peripheral blood mononuclear cells of asthmatic patients is suppressed by T-440: Relation to phosphodiesterase inhibition. J Pharmacol Exp Ther 1996;279:240-246.
32. Essayan DM, Kagey-Sobotka A, Lichtenstein LM, Huang SK. Differential regulation of human antigen-specific Th1 and Th2 lumphocyte responsees by isozyme selective cyclic nucleotide phosphodiesterase inhibitors. J Pharmacol Exp Ther 1997;282:505-512.
33. Souness JE, Rao S. Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. Cell Signal 1997;9(3-4):227-236.
34. Duplantier AJ, Biggers MS, Chambers RJ, Cheng JB, Cooper K, Damon DB, Eggler JF, Kraus KG, Marfat A, Masamune H, Pillar JS, Shirley JT, Umland JP, Watson JW. Biarylcarboxylic acids and -amides: Inhibition of phosphodiesterase type IV versus [3H]rolipram binding activity and their relationship to emetic behavior in the ferret. J Med Chem 1996;39(1):120-125.
35. Giembycz MA. 4D or not 4D-The emetogenic basis of PDE4 inhibitors uncovered? Trends Pharmacol Sci 2002;23(12):548.
36. David M, Zech K, Seiberling M, Weimar C, Bethke TD. Roflumilast, a novel, oral, selective PDE4 inhibitor, shows high absolute bioavailability. J Allergy Clin Immunol 2004;113(2):S220-S221.
37. Huennemeyer A, Hauns B, David M, Böhmer G, Fux R, Gleiter CH, Waitzinger J, Zech K, Bethke TD. Pharmacokinetics and safety of Roflumilast, a once-daily, oral, selective PDE4 inhibitor, and its active metabolite Roflumilast N-oxide in healthy subjects. J Allergy Clin Immunol 2004;13(2):S222.
38. Giembycz MA. Cilomilast: A second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs 2001;10(7):1361-1379.
39. Li L, Yee C, Beavo JA. CD3- and CD28-dependent induction of PDE7 required for T cell activation. Science 1999;283:848-851.
40. Perez-Torres S, Miro X, Palacios JM, Cortes R, Puigdomenech P, Mengod G. Phosphodiesterase type 4 isozymes expression in human brain examined by in situ hybridization histochemistry and [3H]rolipram binding autoradiography. Comparison with monkey and rat brain. J Chem Neuroanat 2000;20(3-4):349-374.
41. Houslay MD, Sullivan M, Bolger GB. The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family: Intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and antidepressant actions. Adv Pharmacol 1998;44:225-342.
42. Xu RX, Hassell AM, Vanderwall D, Lambert MH, Holmes WD, Luther MA, Rocque WJ, Milburn MV, Zhao Y, Ke H, Nolte RT. Atomic structure of PDE4: Insights into phosphodiesterase mechanism and specificity. Science 2000;288(5472):1822-1825.
43. Dym O, Xenarios I, Ke H, Colicelli J. Molecular docking of competitive phosphodiesterase inhibitors. Mol Pharmacol 2002;61(1):20-25.
44. Lee ME, Markowitz J, Lee JO, Lee H. Crystal structure of phosphodiesterase 4D and inhibitor complex(1). FEBS Lett 2002;530(1-3):53-58.
45. Huai Q, Wang H, Sun Y, Kim HY, Liu Y, Ke H. Three-dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity. Structure (Camb) 2003;11(7):865-873.
46. Xu RX, Rocque WJ, Lambert MH, Vanderwall DE, Luther MA, Nolle RT. Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram. J Mol Biol 2004;337:355-365.
47. Bloom TJ, Beavo JA. Identification and tissue-specific expression of PDE7 phosphodiesterase splice variants. PNAS 1996;93:14188-14192.
48. Miró X, Pérez-Torres S, Palacios JM, Puigdoménech P, Mengod G. Differential distribution of cAMP specific phosphodiesterase 7 A mRNA in rat brain and peripheral organs. Synapse 2001;40:201-214.
49. Glavas NA, Ostenson C, Scaefer JB, Vasta V, Beavo JA. T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1 and 7A3. PNAS 2001;98:6319-6324.
50. Smith SJ, Brookes-Fazakerley S, Donnelly LE, Barnes PJ, Barnelle MS, Giembycz MA. Ubiquitous expression of phosphodiesterase 7A in human proinflammatory and immune cells. Am J Physiol Lung Cell Mol Physiol 2003;284:L279-L289.
51. Han P, Zhu X, Michaeli T. Alternative splicing of the high affinity cAMP-specific phosphodiesterase (PDE7A) mRNA in human skeletal muscle and heart. J Biol Chem 1997;272(26):16152-16157.
52. Bristol-Myers Squibb Co. Purine inhibitors of PDE7. WO 02/102314 A2 2002.
53. Warner-Lambert Company. Truncated phosphodiesterase-7 polipeptides. EP 1 195 435 A1 2002.
54. Hetman JM, Soderling SH, Glavas NA, Beavo JA. Cloning and characterization of PDE7B a cAMP-specific phosphodiesterase. PNAS 2000;97:472-473.
55. Sasaki T, Kotera J, Yuasa K, Omori K. Identification of human PDE7B, a cAMP-specific phosphodiesterase. Biochem Biophys Res Commun 2000;271(3):575-583.
56. Gardner C, Robas N, Cawkill D, Fidock M. Cloning and characterization of the human and mouse PDE7B, a novel cAMP-specific cyclic nucleotide phosphodiesterase. Biochem Biophys Res Commun 2000;272:186-192.
57. Nakata A, Ogawa K, Sasaki T, Koyama N, Wada K, Kotera J, Kikkawa H, Omori K, Kaminuma O. Potential role of phosphodiesterase 7 in human T cell function: Comparative effects of two phosphodiesterase inhibitors. Clin Exp Immunol 2002;128:460-466.
58. Lingsong L, et al. CD3- and CD28-dependent induction of PDE7 required for T cell activation. Science 1999;283:848-851.
59. Giembycz MA. Phosphodiesterase 4 inhibitors and the treatment of asthma: Where are we now and where do we go from here? Drugs 2000;59:193-212.
60. Barnette MS, Underwood DC. New phosphodiesterase inhibitors as therapeutics for the treatment of chronic lung disease. Curr Opin Pulm Med 2000;6(2):164-169.
61. Souness JE, Aldous D, Sargent C. Immunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors. Immunopharmacology 2000;47:127-162.
62. Burnouf C, Pruniaux MP. Recent advances in PDE4 inhibitors as immunoregulators and anti-inflammatory drugs. Curr Pharm Des 2002;8(14):1255-1296.
63. Suzumura A, Ito A, Yoshikawa M, Sawada M. Ibudilast suppresses TNFalpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain Res 1999;837:203-212.
64. Belayev L, Busto R, Ikeda M, Rubin LL, Kajiwara A, Morgan L, Ginsberg MD. Protection against blood-brain barrier disruption in focal cerebral ischemia by the type IV phosphodiesterase inhibitor BBB022: A quantitative study. Brain Res 1998;787(2):277-285.
65. Bielekova B, Lincoln A, McFarland H, Martin R. Therapeutic potential of phosphodiesterase-4 and -3 inhibitors in Th1-medialed autoimmune diseases. J Immunol 2000;164(2):1117-1124.
66. Dyke HJ, Montana JG. Update on the therapeutic potential of PDE4 inhibitors. Expert Opin Investig Drugs 2002;11(1):1-13.
67. Zeller E, Stief HJ, Pflug B, Sastre-y-Hernandez M. Results of a phase II study of the antidepressant effect of rolipram. Pharmacopsychiatry 1984;17(6):188-190.
68. Abbas N, Zou LP, Pelidou SH, Winblad B, Zhu J. Protective effect of Rolipram in experimental autoimmune neuritis: Protection is associated with down-regulation of IFN-gamma and inflammatory chemokines as well as up-regulation of IL-4 in peripheral nervous system. Autoimmunity 2000;32(2):93-99.
69. Zou LP, Deretzi G, Pelidou SH, Levi M, Wahren B, Quiding C, van der Meide P, Zhu J. Rolipram suppresses experimental autoimmune neuritis and prevents relapses in Lewis rats. Neuropharmacology 2000;39(2):324-333.
70. Zhang B, Yang L, Konishi Y, Maeda N, Sakanaka M, Tanaka J. Suppressive effects of phosphodiesterase type IV inhibitors on rat cultured microglial cells: Comparison with other types of cAMP-elevating agents. Neuropharmacology 2002;42(2):262-269.
71. Jimenez JL, Punzon C, Navarro J, Munoz-Fernandez MA, Fresno M. Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappaB and nuclear factor of activated T cells activation. J Pharmacol Exp Ther 2001;299(2):753-759.
72. Souness JE, Houghton C, Sardar N, Withnall MT. Suppression of anti-CDS-induced interleukin-4 and interleukin-5 release from splenocytes of Mesocestoides corti-infected BALB/c mice by phosphodiesterase 4 inhibitors. Biochem Pharmacol 1999;58(6):991-999.
73. Cho JY, Park JS, Baik KU, Lee JG, Kim HP, Yoo ES, Park MH. Differential effect of phosphodiesterase IV inhibitor RP73401 on various inflammatory and immune responses relevant to rheumatoid arthritis. Pharmacol Res 2004;49(5):423-431.
74. Dinter H, Tse J, Halks-Miller M, Asarnow D, Onuffer J, Faulds D, Mitrovic B, Kirsch G, Laurent H, Esperling P, Seidelmann D, Ottow E, Schneider H, Tuohy VK, Wachtel H, Perez HD. The type IV phosphodiesterase specific inhibitor mesopram inhibits experimental autoimmune encephalomyelitis in rodents. J Neuroimmunol 2000;108(1-2):136-146.
75. Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 2001;297(1):267-279.
76. Brideau C, Van Staden C, Styhler A, Rodger IW, Chan CC. The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor-alpha and leukotriene B4 in a novel human whole blood assay. Br J Pharmacol 1999;126(4):979-988.
77. Claveau D, Chen S, O'Keefe S, Zaller DM, Styhler A, Liu S, Huang Z, Nicholson DW, Mancini JA. Preferential inhibition of Th1, but not Th2 cytokines by L-826,141 in vitro, a potent and selective PDE4 inhibitor. J Pharmacol Exp Ther 2004;310(2):752-760.
78. Bruno O, Brullo C, Arduino N, Schenone S, Ranise A, Bondavalli F, Ottonello L, Dapino P, Dallegri F. Synthesis and biological evaluation of neutrophilic inflammation inhibitors. IL Farmaco 2004;59(3):223-235.
79. Boichot E, Wallace JL, Germain N, Corbel M, Lugnier C, Lagente V, Bourguignon JJ. Anti-inflammatory activities of a new series of selective phosphodiesterase 4 inhibitors derived from 9-benzyladenine. J Pharm Exp Ther 2000;292:647-653.
80. Reimund JM, Raboisson P, Pinna G, Lugnier C, Bourguignon JJ, Muller CD. Anti-TNF-alpha properties of new 9-benzyladenine derivatives with selective phosphodiesterase-4-inhibiting properties. Biochem Biophys Res Commun 2001;288(2):427-434.
81. Raboisson P, Lugnier C, Muller C, Reimund JM, Schultz D, Pinna G, Le Bee A, Basaran H, Desaubry L, Gaudiot F, Seloum M, Bourguignon JJ. Design, synthesis and structure-activity relationships of a series of 9-substituted adenine derivatives as selective phosphodiesterase type-4 inhibitors. Eur J Med Chem 2003;38(2):199-214.
82. Huai Q, Liu Y, Francis SH, Corbin JD, Ke H. Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity. J Biol Chem 2004;279(13):13095-13101.
83. Kambayashi T, Wallin RP, Ljunggren HG. cAMP-elevating agents suppress dendritic cell function. J Leukoc Biol 2001;70(6):903-910.
84. Kishi Y, Ohta S, Kasuya N, Sakita S, Ashikaga T, Isobe M. Ibudilast: A non-selective PDE inhibitor with multiple actions on blood cells and the vascular wall. Cardiovasc Drug Rev 2001;19(3):215-225.
85. Fujimoto T, Sakoda S, Fujimura H, Yanagihara T. Ibudilast, a phosphodiesterase inhibitor, ameliorates experimental autoimmune encephalomyelitis in Dark August rats. J Neuroimmunol 1999;95(1-2):35-42.
86. Suzumura A, Ito A, Mizuno T. Phosphodiesterase inhibitors suppress IL-12 production with microglia and T helper 1 development. Mult Scler 2003;9(6):574-578.
87. Mizuno T, Kurotani T, Komatsu Y, Kawanokuchi J, Kato H, Mitsuma N, Suzumura A. Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. Neuropharmacology 2004;46(3):404-411.
88. Kaminuma O, Mon A, Wada K, Kikkawa H, Ikezawa K, Suko M, Okudaira H. A selective type 4 phosphodiesterase inhibitor, T-440, modulates intracellular cyclic AMP level and interleukin-2 production of Jurkat cells. Immunopharmacology 1998;38(3):247-252.
89. Van der Mey M, Boss H, Hatzelmann A, Van der Laan IJ, Sterk GJ, Timmerman H. Novel selective PDE4 inhibitors. 3. In vivo antiinflammatory activity of a new series of N-substituted cis-tetra- and cis-hexahydrophthalazinones. J Med Chem 2002;45(12):2520-2525.
90. Huang Z, Ducharme Y, Macdonald D, Robichaud A. The next generaion of PDES inhibitors. Current Opinion Chem Biol 2001;5:432-438.
91. Celltech Chiroscience Ltd: WO0174786. PDE7 inhibitors. Exp Op Therapeutic Patents 2002;12(4):601-603.
92. Martinez A, Castro A, Gil C, Miralpeix M, Segarra V, Domenech T, Beleta J, Palacios JM, Ryder H, Miro X, Bonet C, Casacuberta JM, Azorin F, Pina B, Puigdomenech P. Benzyl derivatives of 2,1,3-benzo- and benzothieno[3,2-a] thiadiazine 2,2-dioxides: First phosphodiesterase 7 inhibitors. J Med Chem 2000;43(4):683-689.
93. Castro A, Abasolo MI, Gil C, Segarra V, Martinez A. CoMFA of benzyl derivatives of 2,1,3-benzo and benzothieno[3,2-alpha]thiadiazine 2,2-dioxides: Clues for the design of phosphodiesterase 7 inhibitors. Eur J Med Chem 2000;36(4):333-338.
94. Barnes MJ, et al. Synthesis and structure-activity relationships of guanine analogues as phosphodiesterase 7 (PDE7) inhibitors. Bioorganic Med Chem Lett 2001;11:1081-1083.
95. Warner-Lambert Company. New Thiadiazoles and their use as phosphodiesterase 7 inhibitors. EP 1 193 261 A1 2000.
96. Warner-Lambert Company. Spirotricyclic derivatives and their use as phosphodiesterase-7 inhibitors. US 2002/0198198 A1 2002.
97. Bykgulden Lomberg Chemische Farbrik GMBH. Dihydroisoquinolines as novel phosphodiesterase inhibitors. WO 02/40449 A1 2002.
98. Bykgulden Lomberg Chemische Farbrik GMBH. Dihydroisoquinolines as novel phosphodiesterase inhibitors. WO 02/40450 A1 2002.
99. SmithKline Beecham Corp. Compounds and their use as PDE inhibitors. US2002/0156064 2002.
100. Bristol-Myers Squibb Co. Pyrimidine inhibitors of PDE7. WO 02/102313 A2 2002.
101. Bristol-Myers Squibb Co. Purine inhibitors of PDE7. WO 02/102314 A2 2002.
102. Pitts WJ, Vaccaro W, Huynh T, Leftheris K, Roberge JY, Barbosa J, Guo J, Brown B, Watson A, Donaldson K, Starling GC, Kiener PA, Poss MA, Dodd JH, Barrish JC. Identification of purine inhibitors of phosphodiesterase 7 (PDE7). Bioorg Med Chem Lett 2004;14(11):2955-2958.
103. Department of Health and Human Services (US GOV). Combined inhibition of phosphodiesterase-4 and phosphodiesterase-3 as a therapy for Th1 mediated autoimmune diseases. WO 02/051502 A1 2002.
104. Bristol-Myers Squibb Co. Dual inhibitors of PDE7 and PDE4. WO 02/088080 A2 2002.
105. Perez Torres S, Mengod G. cAMP-specific phosphodiesterases expression in Alzheimer's diseases brains. Int Congress Series 2003;1251:127-138.