Phosphodiesterase 4-targeted treatments for autoimmune diseases

BMC Medicine

Alice B Gottlieb¹  Noori Kim¹  Ari M Goldminz¹  Neal Kumar¹ 

[1] Department of Dermatology, Tufts Medical Center, 800 Washington Street #114, Boston, MA, 02111, USA

关键词: SLE;    Psoriasis;    PDE4;    Dermatitis;    Crohn’s;    Apremilast;    Autoimmune;   

Others  :  857109
DOI  :  10.1186/1741-7015-11-96

 received in 2012-09-21, accepted in 2013-02-11,  发布年份 2013

【 摘 要 】

Advancements in phosphodiesterase (PDE)-targeted therapies have shown promise in recent years for treating patients with a variety of autoimmune diseases. This review summarizes the development of PDE4 inhibitors and the associated literature with a focus on treatments for autoimmune diseases. After the initial investigations of the prototypic PDE inhibitor, rolipram, more selective inhibitors targeting the PDE4 isozyme have been developed. With phase II and phase III clinical trials currently underway to evaluate the safety and efficacy of the latest generation of PDE4 inhibitors, namely apremilast, a new class of treatments may be around the corner for patients suffering from chronic, autoimmune diseases.

【 授权许可】

   
2013 Kumar et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Sutherland EW, Rall T: The properties of an adenine ribonucleotide produced with cellular particles, ATP, mg, and epinephrine or glucagon. J Am Chem Soc 1957, 79:3608-3608.
• [2]Rall T, Sutherland E: Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles. J Biol Chem 1958, 232:1077.
• [3]Henney CS, Lichtenstein LM: The role of cyclic AMP in the cytolytic activity of lymphocytes. J Immunol 1971, 107:610-612.
• [4]Henney CS, Bourne HR, Lichtenstein LM: The role of cyclic 3′, 5′ adenosine monophosphate in the specific cytolytic activity of lymphocytes. J Immunol 1972, 108:1526.
• [5]Bourne H, Weinstein Y, Melmon K, Lichtenstein L, Henney C, Shearer G: Modulation of inflammation and immunity by cyclic AMP. Science 1974, 184:19-28.
• [6]Essayan DM: Cyclic nucleotide phosphodiesterase (PDE) inhibitors and immunomodulation. Biochem Pharmacol 1999, 57:965-973.
• [7]Giembycz MA, Corrigan C, Seybold J, Newton R, Barnes P: 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 1945, 1996:118.
• [8]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, 128:1393-1398.
• [9]Hidi R, Timmermans S, Liu E, Schudt C, Dent G, Holgate ST, Djukanović R: Phosphodiesterase and cyclic adenosine monophosphate-dependent inhibition of T-lymphocyte chemotaxis. Eur Respir J 2000, 15:342-349.
• [10]Brideau C, Van Staden C, Styhler A, Rodger IW, Chan CC: The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor-α and leukotriene B4 in a novel human whole blood assay. Br J Pharmacol 1999, 126:979-988.
• [11]Gale DD, Landells LJ, Spina D, Miller AJ, Smith K, Nichols T, Rotshteyn Y, Tonelli A, Lacouture P, Burch RM, Page CP, O’Connor BJ: Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE) 4 inhibitor V11294A in healthy volunteers. Br J Clin Pharmacol 2002, 54:478-484.
• [12]Lipworth BJ: Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 2005, 365:167-175.
• [13]Pieretti S, Dominici L, Di Giannuario A, Cesari N, Dal Piaz V: Local anti-inflammatory effect and behavioral studies on new PDE4 inhibitors. Life Sci 2006, 79:791-800.
• [14]Spina D: PDE4 inhibitors: current status. Br J Pharmacol 2008, 155:308-315.
• [15]Gottlieb A, Strober B, Krueger J, Rohane P, Zeldis JB, Hu CC, Kipnis C: An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast*. Curr Med Res Opin 2008, 24:1529-1538.
• [16]Hoffmann M, Kumar G, Schafer P, Cedzik D, Capone L, Fong KL, Gu Z, Heller D, Feng H, Surapaneni S, Laskin O, Wu A: Disposition, metabolism and mass balance of [14C] apremilast following oral administration. Xenobiotica 2011, 41:1063-1075.
• [17]Man HW, Schafer P, Wong LM, Patterson RT, Corral LG, Raymon H, Blease K, Leisten J, Shirley MA, Tang Y, Babusis DM, Chen R, Stirling D, Muller GW: Discovery of (S)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1, 3-dioxo-2, 3-dihydro-1 H-isoindol-4-yl} acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-α inhibitor. J Med Chem 2009, 52:1522-1524.
• [18]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.
• [19]Dyke H, Montana J: Update on the therapeutic potential of PDE4 inhibitors. Expert Opin Investig Drugs 2002, 11:1.
• [20]Dietsch GN, Dipalma CR, Eyre RJ, Pham TQ, Poole KM, Pefaur NB, Welch WD, Trueblood E, Kerns WD, Kanaly ST, Stirling D, Muller GW: Characterization of the inflammatory response to a highly selective PDE4 inhibitor in the rat and the identification of biomarkers that correlate with toxicity. Toxicol Pathol 2006, 34:39-51.
• [21]GlaxoSmithKline: SB 207499 (ariflo, cilomilast) [9 February 2006]. New drugs application (21–573). 2003. [Pulmonary and allergy drug products advisory committee. Nonclinical findings] http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3976T1.doc webcite
• [22]Man HW, Schafer P, Wong LM, Patterson RT, Corral LG, Raymon H, Tang Y: Discovery of (S)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1, 3-dioxo-2, 3-dihydro-1 H-isoindol-4-yl} acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-α inhibitor. J Med Chem 2009, 52:1522-1524.
• [23]Christensen SB, Guider A, Forster CJ, Gleason JG, Bender PE, Karpinski JM, DeWolf WE Jr, Barnette MS, Underwood DC, Griswold DE, Cieslinski LB, Burman M, Bochnowicz S, Osborn RR, Manning CD, Grous M, Hillegas LM, Bartus JO, Ryan MD, Eggleston DS, Haltiwanger RC, Torphy TJ: 1, 4-cyclohexanecarboxylates: potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma. J Med Chem 1998, 41:821-835.
• [24]Wachtel H: Potential antidepressant activity of rolipram and other selective cyclic adenosine 3′,5′-monophosphate phosphodiesterase inhibitors. Neuropharmacology 1983, 22:267-272.
• [25]Davis CW: Assessment of selective inhibition of rat cerebral cortical calcium-independent and calcium-dependent phosphodiesterases in crude extracts using deoxycyclic AMP and potassium ions. Biochim Biophys Acta 1984, 797:354-362.
• [26]O’Donnell JM, Zhang HT: Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci 2004, 25:158-163.
• [27]Calverley PMA, Fabbri LM, Rabe KF, Mosberg H: Roflumilast in the treatment of COPD: a pooled safety analysis. Eur Respir J 2010. Abstract P4001
• [28]Calverley P, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ: Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009, 374:685.
• [29]Omar B, Zmuda-Trzebiatowska E, Manganiello V, Goransson O, Degerman E: Regulation of AMP-activated protein kinase by cAMP in adipocytes: roles for phosphodiesterases, protein kinase B, protein kinase A, Epac and lipolysis. Cell Signal 2009, 21:760-766.
• [30]Ong WK, Gribble FM, Reimann F, Lynch MJ, Houslay MD, Baillie GS, Furman BL, Pyne NJ: The role of the PDE4D cAMP phosphodiesterase in the regulation of glucagon-like peptide-1 release. Br J Pharmacol 2009, 157:633-644.
• [31]Middleton E Jr, Kandaswami C, Theoharides TC: The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 2000, 52:673-751.
• [32]Peluso MR: Flavonoids attenuate cardiovascular disease, inhibit phosphodiesterase, and modulate lipid homeostasis in adipose tissue and liver. Exp Biol Med 2006, 231:1287-1299.
• [33]Guabiraba R, Campanha-Rodrigues AL, Souza ALS, Santiago HC, Lugnier C, Alvarez-Leite J, Lemos VS, Teixeira MM: The flavonoid dioclein reduces the production of pro-inflammatory mediators in vitro by inhibiting PDE4 activity and scavenging reactive oxygen species. Eur J Pharmacol 2010, 633:85-92.
• [34]Ribeiro S, Horuk R: The clinical potential of chemokine receptor antagonists. Pharmacol Ther 2005, 107:44-58.
• [35]Gonçalves RL, Lugnier C, Keravis T, Lopes MJ, Fantini FA, Schmitt M, Cortes SF, Lemos VS: The flavonoid dioclein is a selective inhibitor of cyclic nucleotide phosphodiesterase type 1 (PDE1) and a cGMP-dependent protein kinase (PKG) vasorelaxant in human vascular tissue. Eur J Pharmacol 2009, 620:78-83.
• [36]Lowes MA, Bowcock AM, Krueger JG: Pathogenesis and therapy of psoriasis. Nature 2007, 445:866-873.
• [37]Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V, Freund Y, Kimura R, Maples KR, Plattner JJ: Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett 2009, 19:2129-2132.
• [38]Nazarian R, Weinberg JM: AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis. Curr Opin Investig Drugs 2009, 10:1236-1242.
• [39]Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M: Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets 2007, 6:17-26.
• [40]Papp K, Cather JC, Rosoph L, Sofen H, Langley RG, Matheson RT, Hu C, Day RM: Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial. Lancet 2012, 380:738-746.
• [41]Schett G, Wollenhaupt J, Papp K, Joos R, Rodrigues JF, Vessey AR, Hu C, Stevens R, de Vlam KL: Oral apremilast in the treatment of active psoriatic arthritis: results of a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 2012, 64:3156-3167.
• [42]Baraliakos X, Hermann KG, Braun J: Imaging in axial spondyloarthritis: diagnostic problems and pitfalls. Rheum Dis Clin North Am 2012, 38:513-522.
• [43]Baraliakos X, Listing J, Rudwaleit M, Sieper J, Braun J: The relationship between inflammation and new bone formation in patients with ankylosing spondylitis. Arthritis Res Ther 2010, 10:104.
• [44]Chiowchanwisawakit P, Lambert RGW, Conner-Spady B, Maksymowych WP: Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis. Arthritis Rheum 2011, 63:2215-2225.
• [45]Machado P, Landewé R, Lie E, Kvien TK, Braun J, Baker D, van der Heijde D: Ankylosing spondylitis disease activity score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis 2011, 70:47-53.
• [46]Visvanathan S, Wagner C, Marini J, Baker D, Gathany T, Han J, van der Heijde D, Braun J: Inflammatory biomarkers, disease activity and spinal disease measures in patients with ankylosing spondylitis after treatment with infliximab. Ann Rheum Dis 2008, 67:511-517.
• [47]Visvanathan S, van der Heijde D, Deodhar A, Wagner C, Baker DG, Han J, Braun J: Effects of infliximab on markers of inflammation and bone turnover and associations with bone mineral density in patients with ankylosing spondylitis. Ann Rheum Dis 2009, 68:175-182.
• [48]Braun J, Van den Berg R, Baraliakos X, Boehm H, Burgos-Vargas R, Collantes-Estevez E, Dagfinrud H, Dijkmans B, Dougados M, Emery P, Geher P, Hammoudeh M, Inman RD, Jongkees M, Khan MA, Kiltz U, Kvien T, Leirisalo-Repo M, Maksymowych WP, Olivieri I, Pavelka K, Sieper J, Stanislawska-Biernat E, Wendling D, Ozgocmen S, van Drogen C, van Royen B, van der Heijde D: 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 2011, 70:896.
• [49]van der Heijde D, Sieper J, Maksymowych WP, Dougados M, Burgos-Vargas R, Landewé R, Rudwaleit M, Braun J: 2010 update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis. Ann Rheum Dis 2011, 70:905-908.
• [50]Pathan E, Abraham S, Van-Rossen L: Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing spondylitis. Ann Rheum DisIn press
• [51]Brennan FM, Jackson A, Chantry D, Maini R, Feldmann M: Inhibitory effect of TNFα antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 1989, 334:244-247.
• [52]Feldmann M, Maini RN: TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med 2003, 9:1245-1250.
• [53]Sekut L, Yarnall D, Stimpson S, Noel LS, Bateman-Fite R, Clark RL, Brackeen MF, Menius JA Jr, Connolly KM: Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation. Clin Exp Immunol 1995, 100:126-132.
• [54]McCann FE, Palfreeman AC, Andrews M, Perocheau DP, Inglis JJ, Schafer P, Feldmann M, Williams RO, Brennan FM: Apremilast, a novel PDE4 inhibitor, inhibits spontaneous production of tumour necrosis factor-alpha from human rheumatoid synovial cells and ameliorates experimental arthritis. Arthritis Res Ther 2010, 12:R107. BioMed Central Full Text
• [55]Schett G, Wollenhaupt J, Papp K: Apremilast is active in the treatment of rheumatoid arthritis [abstract 1258]. Arthritis Rheum 2009, 60:S10.
• [56]Cush J, Research Institute: The controlled trial of Apremilast for rheumatoid arthritis treatment. http://clinicaltrials.gov/show/NCT01250548 webcite
• [57]Rahman A, Isenberg DA: Systemic lupus erythematosus. N Engl J Med 2008, 358:929-939.
• [58]Monneaux F, Muller S: Molecular therapies for systemic lupus erythematosus: clinical trials and future prospects. Arthritis Res Ther 2010, 11:234.
• [59]Keravis T, Monneaux F, Yougbaré I, Gazi L, Bourguignon JJ, Muller S, Lugnier C: Disease progression in MRL/lpr lupus-prone mice is reduced by NCS 613, a specific cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor. PLoS One 2012, 7:e28899.
• [60]Park M, Fontana J, Babaali H, Gilbert-McClain LI, Stylianou M, Joo J, Moss J, Manganiello VC: Steroid-sparing effects of pentoxifylline in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse lung Dis 2009, 26:121.
• [61]Baughman RP, Judson MA, Ingledue R, Craft NL, Lower EE: Efficacy and safety of apremilast in chronic cutaneous sarcoidosis. Arch Dermatol 2012, 148:262-264.
• [62]Podolsky DK: Inflammatory bowel disease. N Engl J Med 2002, 347:417-429.
• [63]Keshavarzian A, Mutlu E, Guzman JP, Forsyth C, Banan A: Phosphodiesterase 4 inhibitors and inflammatory bowel disease: emerging therapies in inflammatory bowel disease. Exp Opin Invest Drugs 2007, 16:1489-1506.
• [64]Hollander D: Crohn’s disease–a permeability disorder of the tight junction? Gut 1988, 29:1621-1624.
• [65]Gordon J, Prothero J, Thornton C, Pickard KM, Di Sabatino A, Goggin PM, Pender SL, Macdonald TT: CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-α and MMP-3 production in patients with inflammatory bowel disease. J Crohns Colitis 2009, 3:175-182.
• [66]Schreiber S, Nikolaus S, Hampe J: Activation of nuclear factor κB in inflammatory bowel disease. Gut 1998, 42:477-484.
• [67]Cooper KD: Atopic dermatitis: recent trends in pathogenesis and therapy. J Invest Dermatol 1994, 102:128-137.
• [68]Butler JM, Chan SC, Stevens S, Hanifin JM: Increased leukocyte histamine release with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis. J Allergy Clin Immunol 1983, 71:490-497.
• [69]Harada D, Ikeda Y, Nosaka Y, Kobayashi K, Manabe H: Curative effects of phosphodiesterase 4 inhibitors cilomilast, roflumilast, and rolipram in dermatitis mouse model. J Dermatol Sci 2008, 51:215-219.
• [70]Harada D, Takada C, Nosaka Y, Takashima Y, Kobayashi K, Takaba K, Manabe H: Effect of orally administered KF66490, a phosphodiesterase 4 inhibitor, on dermatitis in mouse models. Int Immunopharmacol 2009, 9:55-62.
• [71]Samrao A, Berry TM, Goreshi R, Simpson EL: A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol 2012, 812:v1.
• [72]Luterman JD, Haroutunian V, Yemul S, Ho L, Purohit D, Aisen PS, Mohs R, Pasinetti GM: Cytokine gene expression as a function of the clinical progression of alzheimer disease dementia. Arch Neurol 2000, 57:1153.
• [73]Abdi A, Sadraie H, Dargahi L, Khalaj L, Ahmadiani A: Apoptosis inhibition can be threatening in Aβ-induced neuroinflammation, through promoting cell proliferation. Neurochem Res 2011, 36:39-48.
• [74]Mattson MP: Pathways towards and away from alzheimer’s disease. Nature 2004, 430:631-639.
• [75]Wang C, Yang XM, Zhuo YY, Zhou H, Lin HB, Cheng YF, Xu JP, Zhang HT: The phosphodiesterase-4 inhibitor rolipram reverses Aβ-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats. Int J Neuropsychopharmacol 2011, 1:1-18.
• [76]Khoruts A, Miller SD, Jenkins MK: Neuroantigen-specific Th2 cells are inefficient suppressors of experimental autoimmune encephalomyelitis induced by effector Th1 cells. J Immunol 1995, 155:5011.
• [77]Sommer N, Martin R, McFarland H, Quigley L, Cannella B, Raine CS, Scott DE, Löschmann PA, Racke MK: Therapeutic potential of phosphodiesterase type 4 inhibition in chronic autoimmune demyelinating disease. J Neuroimmunol 1997, 79:54-61.
• [78]Hartung HP, Kieseier BC: The role of matrix metalloproteinases in autoimmune damage to the central and peripheral nervous system. J Neuroimmunol 2000, 107:140-147.
• [79]Kieseier BC, Kiefer R, Clements JM, Miller K, Wells GM, Schweitzer T, Gearing AJ, Hartung HP: Matrix metalloproteinase-9 and-7 are regulated in experimental autoimmune encephalomyelitis. Brain 1998, 121:159-166.
• [80]Sánchez AJ, Puerta C, Ballester S, González P, Arriaga A: Rolipram impairs NF-κB activity and MMP-9 expression in experimental autoimmune encephalomyelitis. J Neuroimmunol 2005, 168:13-20.