Journal of Medicinal Chemistry
Article
(10) Giembycz, M. A.; Smith, S. J. Phosphodiesterase 7A: a new
therapeutic target for alleviating chronic inflammation? Curr. Pharm.
Des. 2006, 12, 3207−3220.
(11) Miro, X.; Perez-Torres, S.; Palacios, J. M.; Puigdomenech, P.;
Mengod, G. Differential distribution of cAMP-specific phosphodies-
terase 7A mRNA in rat brain and peripheral organs. Synapse 2001, 40,
201−214.
ACKNOWLEDGMENTS
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The authors gratefully acknowledge the financial support of
Ministry of Science and Innovation (MICINN), Projects Nos.
SAF2009-13015-C02-01, SAF2009-13015-C02-02, SAF2010-
16365, SAF2009-1152, CTQ2009-07664, and PI10-01874;
Instituto de Salud Carlos III (ISCiii), Project No. RD07/
(12) Sasaki, T.; Kotera, J.; Omori, K. Novel alternative splice variants
of rat phosphodiesterase 7B showing unique tissue-specific expression
and phosphorylation. Biochem. J. 2002, 361, 211−220.
(13) Reyes-Irisarri, E.; Perez-Torres, S.; Mengod, G. Neuronal
expression of cAMP-specific phosphodiesterase 7B mRNA in the rat
brain. Neuroscience 2005, 132, 1173−1185.
0060/0015 (RETICS program) and CIBERNED; Fundacion
́
́
Espanola para la Ciencia y la Tecnologia (FECYT), Project No.
̃
FCT-09-INC-0367. M.R. and D.I.P. acknowledge pre- and
postdoctoral fellowships from the CSIC (JAE program),
respectively. BRAINco Biopharma is acknowledged.
(14) 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.
(15) Gil, C.; Campillo, N. E.; Perez, D. I.; Martinez, A.
Phosphodiesterase 7 (PDE7) inhibitors as new drugs for neurological
and inflammatory disorders. Expert Opin. Ther. Pat. 2008, 18, 1127−
1139.
ABBREVIATIONS USED
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ADME, absorption, distribution, metabolism, and excretion; BBB,
blood−brain barrier; cAMP, cyclic adenosine 3′,5′-monophos-
phate; CFA, complete Freund’s adjuvant; cGMP, cyclic guanosine
3′,5′-monophosphate; CNS, central nervous system; DCC, N,N′-
dicyclohexylcarbodiimide; DMEM, Dulbecco’s modified Eagle’s
medium; DMSO, dimethyl sulfoxide; EAE, experimental auto-
immune encephalomyelitis; EDTA, ethylenediaminetetraacetic
acid; ES, electrospray; FBS, fetal bovine serum; FP, fluorescence
polarization; GFAP, glial fibrillary acidic protein; GM-CSF,
granulocyte-macrophage colony-stimulating factor; HAMS,
Ham’s F-12 nutrient mixture; HBSS, Hank’s balanced salt
solution; IC50, inhibitory concentration 50; IMAP, immobilized
metal ion affinity-based fluorescence polarization, MOG, myelin
oligodendrocyte glycoprotein; mRNA, messenger ribonucleic acid;
MS, mass spectrometry; MTT, 3-[4, 5-dimethylthiazol-2-yl]-2,5-
diphenyltetrazolium bromide; NMR, nuclear magnetic resonance;
LPS, lipopolysaccharide; PAMPA, parallel artificial membrane
permeability assay; PBL, porcine polar brain lipid; PBS, phosphate
buffer saline; PDE, phosphodiesterase; PDVF, polyvinylidene
difluoride; PyBOP, benzotriazol-1-yloxytripyrrolidinophospho-
nium hexafluorophosphate; SAR, structure−activity relationship;
SD, standard deviation; SDS, sodium dodecyl sulfate; SPA,
scintillation proximity assay; TEA, triethylamine; THF, tetrahy-
drofuran; UV, ultraviolet light
(16) Martinez, A.; Castro, A.; Gil, C.; Miralpeix, M.; Segarra, V.;
Domenech, T.; Beleta, J.; Palacios, J. M.; Ryder, H.; Miro, X.; Bonet,
C.; Casacuberta, J. M.; 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,
683−689.
(17) Castro, A.; Jerez, M. J.; Gil, C.; Martinez, A. Cyclic nucleotide
phosphodiesterases and their role in immunomodulatory responses:
advances in the development of specific phosphodiesterase inhibitors.
Med. Res. Rev. 2005, 25, 229−244.
(18) Morales-Garcia, J.; Redondo, M.; Gil, C.; Alonso-Gil, S.;
Martinez, A.; Santos, A.; Perez-Castillo, A. Phosphodiesterase 7
inhibition preserves dopaminergic neurons in cellular and rodent
models of Parkinson disease. PLoS One 2011, 6, e17240.
(19) Paterniti, I.; Mazzon, E.; Gil, C.; Impllizzari, D.; Palomo, V.;
Redondo, M.; Perez, D. I.; Esposito, E.; Martinez, A.; Cuzzocrea, S.
PDE 7 inhibitors: new potential drugs for the therapy of spinal cord
injury. PLoS One 2011, 6, e15937.
(20) Redondo, M.; Zarruk, J. G.; Ceballos, P.; Perez, D. I.; Perez, C.;
Perez-Castillo, A.; Moro, M. A.; Brea, J.; Val, C.; Cadavid, M. I.; Loza,
M. I.; Campillo, N. E.; Martinez, A.; Gil, C. Neuroprotective efficacy of
quinazoline type phosphodiesterase 7 inhibitors in cellular cultures and
experimental stroke model. Eur. J. Med. Chem. 2012, 47, 175−185.
(21) Jerez, M. J.; Castro, A.; Gil, C.; Martinez, A. Development of a
pharmacophoric model for specific PDE7 inhibitors. Drugs Future
2004, 29 (Suppl. A), 129.
REFERENCES
■
(1) Essayan, D. M. Cyclic nucleotide phosphodiesterase (PDE)
inhibitors and immunomodulation. Biochem. Pharmacol. 1999, 57,
965−973.
(2) Conti, M.; Jin, S. L. The molecular biology of cyclic nucleotide
phosphodiesterases. Prog. Nucleic Acid Res. Mol. Biol. 1999, 63, 1−38.
(3) Bender, A. T.; Beavo, J. A. Cyclic nucleotide phosphodiesterases:
molecular regulation to clinical use. Pharmacol. Rev. 2006, 58, 488−
520.
(22) Gil, C.; Castro, A.; Jerez, M. J.; Ke, H.; Wang, H.; Ballester, S.;
́
Gonzalez-García, C.; Martínez, A. New PDE7 inhibitors leads for
neurodegenerative diseases discovered by using a pharmacophoric
model. Drugs Future 2008, 33 (Suppl. A), 228.
(23) Vaupel, S.; Brutschy, B.; Tarakeshwar, P.; Kim, K. S. Character-
ization of weak NH−pi intermolecular interactions of ammonia with
various substituted pi-systems. J. Am. Chem. Soc. 2006, 128, 5416−5426.
(24) Mohan, N.; Vijayalakshmi, K. P.; Koga, N.; Suresh, C. H.
Comparison of aromatic NH···pi, OH···pi, and CH···pi interactions of
alanine using MP2, CCSD, and DFT methods. J. Comput. Chem. 2010,
31, 2874−2882.
(25) Ke, H.; Wang, H. Crystal structures of phosphodiesterases and
implications on substrate specificity and inhibitor selectivity. Curr. Top.
Med. Chem. 2007, 7, 391−403.
(26) Smith, S. J.; Cieslinski, L. B.; Newton, R.; Donnelly, L. E.;
Fenwick, P. S.; Nicholson, A. G.; Barnes, P. J.; Barnette, M. S.;
Giembycz, M. A. Discovery of BRL 50481 [3-(N,N-dimethylsulfona-
mido)-4-methyl-nitrobenzene], a selective inhibitor of phosphodies-
terase 7: in vitro studies in human monocytes, lung macrophages, and
CD8+ T-lymphocytes. Mol. Pharmacol. 2004, 66, 1679−1689.
(4) Francis, S. H.; Conti, M.; Houslay, M. D. Phosphodiesterases as
Drug Targets; Springer-Verlag: Berlin and Heidelberg, Germany, 2011.
(5) Lugnier, C. Cyclic nucleotide phosphodiesterase (PDE) super-
family: a new target for the development of specific therapeutic agents.
Pharmacol. Ther. 2006, 109, 366−398.
(6) Allison, A. C. Immunosuppressive drugs: the first 50 years and a
glance forward. Immunopharmacology 2000, 47, 63−83.
(7) Houslay, M. D.; Schafer, P.; Zhang, K. Y. Keynote review:
phosphodiesterase-4 as a therapeutic target. Drug Discovery Today
2005, 10, 1503−1519.
(8) Giembycz, M. A. Life after PDE4: overcoming adverse events
with dual-specificity phosphodiesterase inhibitors. Curr. Opin.
Pharmacol. 2005, 5, 238−244.
(9) Conti, M.; Beavo, J. Biochemistry and physiology of cyclic
nucleotide phosphodiesterases: essential components in cyclic
nucleotide signaling. Annu. Rev. Biochem. 2007, 76, 481−511.
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