Phosphodiesterase Inhibitors

Cyclic Nucleotide Phosphodiesterases
Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and/or cGMP. They function in conjunction with adenylyl and guanylyl cyclases to regulate the amplitude and duration of cell signaling mechanisms mediated via cAMP and cGMP. They therefore serve to regulate a range of biological responses to first messengers such as light, hormones, neurotransmitters and odorants. Two classes of functional PDEs (which do not share any sequence homology) are recognized: Class II PDEs have to date only been found in lower eukaryotes and are not as well characterized as Class I PDEs. Class I PDEs are found in all eukaryotic cells, either in the cytoplasm or bound to intracellular organelles or membranes. They all contain an approximately 250 amino acid catalytic domain near the C-terminus that is conserved across families within this class. This overview focuses on the Class I PDEs identified in mammalian cells.
Sequence analyses suggest that there are at least 11 different families of mammalian PDEs, most of which contain more than one gene product. Furthermore, many of these genes can be alternately spliced in a tissue specific manner to give several different mRNAs/proteins with altered regulatory properties or subcellular localization. PDEs are named to precisely identify the isozyme being referenced. For example, MMPDE4A1 refers to the Mus musculus PDE4 family, gene A, splice variant 1.
Each PDE family, and even PDEs within a family, can display different substrate specificities, kinetics, allosteric regulation and subcellular localization. Therefore, the expression profile of PDEs within a given cell will determine which PDEs regulate cyclic nucleotide levels in that cell or subcellular region. The distinct cellular localization and biophysical characteristics of the various PDEs suggest that individual PDEs are individually regulated and play distinct roles in specific physiological processes. For example, the three gene products of the PDE1 family are activated by calcium/calmodulin and are probably inactivated by phosphorylation by protein kinase A and/or calmodulin (CaM) kinase II. They are thought to participate in the feed-forward amplification of neuronal signals. Similarly, PDE2A has been shown to play a role in regulating aldosterone production in adrenal glomerulosa cells through integration of cAMP and cGMP signals. PDE3s, the cGMP-inhibited PDEs, allow cGMP to potentiate a cAMP signal in cells where they are expressed. PDE3A is involved in regulation of platelet aggregation by cGMP, while PDE3B mediates insulin regulation of lipolysis in adipocytes and IGF-1 or leptin inhibition of insulin secretion in pancreatic beta cells. PDE4s (4A, 4B, 4C and 4D) are widely expressed and are likely responsible for modulating a variety of functions, including emesis, lymphocyte-mediated inflammation and follicle stimulating hormone responsiveness in Sertoli cells. PDE5A plays a role in regulating smooth muscle tension in humans, and sildenafil, a selective PDE5A inhibitor, is used as a therapeutic agent to treat erectile dysfunction in man. PDE6A and 6B play a central role in visual phototransduction through rapid modulation of cGMP hydrolysis. PDE7A is induced upon T-cell activation and thought to play a role in modulation of T-cell responsiveness.
The remaining PDEs have only recently been described and specific cellular functions for each isozyme have not been elucidated. Early data suggest that PDE7B may participate in signal transduction in the liver and pancreas. PDE8A is highly expressed in pre-meiotic spermatids, while PDE8B is found almost exclusively in the thyroid. PDE9A is found primarily in the kidney, whereas PDE10A is abundant in the testis and brain. PDE11A is found in skeletal muscle, as well as in the prostate. It is likely that these PDE isozymes play important roles in these tissues.
Beavo, J.A., et al,. Multiple cyclic nucleotide phospho-diesterases. Mol. Pharmacol., 46, 399-405 (1994).
Conti, M., and Jin, S.L.C. The molecular biology of cyclic nucleotide phosphodiesterases. Prog. Nucleic Acid Res. Mol. Biol., 63, 1-38 (2000).
Dousa, T.P., Cyclic-3,5-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney. Kidney Int., 55, 29-62 (1999).
Juilfs, D.M., et al., A subset of olfactory neurons that selectively express cGMP-stimulated phosphodiesterase (PDE2) and guanylyl cyclase-D define a unique olfactory signal transduction pathway. Proc. Natl. Acad. Sci. USA, 94, 3388-3395 (1997).
Li, L., et al., CD3- and CD28-dependent induction of PDE7 required for T cell activation. Science, 283, 848-851 (1999).
Manganiello, V.C., and Degerman, E., Cyclic nucleotide phosphodiesterases: Diverse regulators of cyclic nucleotide signals and inviting molecular targets for novel therapeutic agents. Thromb. Haemost., 82, 407-411 (1999).
Soderling, S.H., and Beavo, J.A., Regulation of cAMP and cGMP signaling: New phosphodiesterases and new functions. Curr. Opin. Cell Biol., 12, 174-179 (2000).
Sonnenburg, W.K., et al., Identification, quantitation, and cellular localization of PDE1 calmodulin-stimulated cyclic nucleotide phosphodiesterases. Methods, 14, 3-19 (1998).
Teixeira, M.M., et al., Phosphodiesterase (PDE)4 inhibitors: Anti-inflammatory drugs of the future? Trends Pharmacol. Sci., 18, 164-170 (1997).
Zhao, A.Z., et al., Recent advances in the study of Ca2+/CaM activated phosphodiesterases: Expression and physiological functions. Adv. Second Messenger Phosphoprotein Res., 31, 237-251 (1997).
Zhao, A.Z., et al., Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J. Clin. Invest., 102, 869-873 (1998).
Zhao, A.Z., et al., Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B. Proc. Natl. Acad. Sci. USA, 94, 3223-3228 (1997).

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208665 Calmidazolium Chloride - CAS 57265-65-3 - Calbiochem A cell-permeable calmodulin antagonist.
231085 Cilostamide - CAS 68550-75-4 - Calbiochem A cell-permeable selective inhibitor of cGMP-inhibited phosphodiesterase (PDE III; IC₅₀ = 70 nM).
324630 EHNA, Hydrochloride - CAS 51350-19-7 - Calbiochem The racemic mixture of a cell-permeable adenine derivative that acts as a PDE II-selective phosphodiesterase inhibitor and adenosine deaminase.
382425 Trequinsin, Hydrochloride - CAS 78416-81-6 - Calbiochem Extremely potent and cell-permeable inhibitor of cGMP-inhibited phosphodiesterase (IC₅₀ = 300 pM) and platelet aggregation in vitro.
410957 3-Isobutyl-1-methylxanthine - CAS 28822-58-4 - Calbiochem 3-Isobutyl-1-methylxanthine, CAS 28822-58-4, is a cell-permeable, non-specific inhibitor of cAMP and cGMP phosphodiesterases (IC50 = 2-50 µM)., A cell-permeable, non-specific inhibitor of cAMP and cGMP phosphodiesterases (IC₅₀ = 2-50 µM).
454202 8-Methoxymethyl-3-isobutyl-1-methylxanthine - CAS 78033-08-6 - Calbiochem A cell-permeable selective inhibitor of Ca2+-calmodulin-dependent phosphodiesterase (PDE I; IC₅₀ = 4 µM).
475250 4-{[3ʹ,4ʹ-(Methylenedioxy)benzyl]amino}-6-methoxyquinazoline
475840 Milrinone - CAS 78415-72-2 - Calbiochem A cell-permeable, selective inhibitor of cGMP-inhibited phosphodiesterase (PDE III; IC₅₀ = 300 nM).
481908 Nicotinamide Phosphoribosyltransferase Inhibitor, FK866 - CAS 658084-64-1 - Calbiochem The Nicotinamide Phosphoribosyltransferase Inhibitor, FK866, also referenced under CAS 658084-64-1, controls the biological activity of Nicotinamide Phosphoribosyltransferase. This small molecule/inhibitor is primarily used for Neuroscience applications.
5.08957 PDE5 Inhibitor, Cpd7a - Calbiochem A cell-permeable, highly potent and selective inhibitor of phosphodiesterase 5 (PDEV; IC₅₀ = 270 pM).
513050 PDE10A Inhibitor, Cpd15 - Calbiochem
524718 Phosphodiesterase Inhibitor Set I - Calbiochem The Phosphodiesterase Inhibitor Set I controls the activity of Phosphodiesterase. This small molecule/inhibitor is primarily used for Cell Signaling applications.
557330 Rolipram - CAS 61413-54-5 - Calbiochem A cell-permeable, selective inhibitor of cAMP-specific phosphodiesterase (PDE IV; IC₅₀ = 800 nM).
557502 Ro-20-1724 - CAS 29925-17-5 - Calbiochem A cell-permeable, selective inhibitor of cAMP-specific phosphodiesterase (PDE IV; IC₅₀ = 2 µM).
681625 W-5, Hydrochloride - CAS 61714-25-8 - Calbiochem A cell-permeable and reversible calmodulin antagonist that inhibits myosin light chain kinase (IC₅₀ = 230 µM) and Ca2+-calmodulin-dependent phosphodiesterase (IC₅₀ = 240 µM).
681629 W-7, Hydrochloride - CAS 61714-27-0 - Calbiochem A cell-permeable and reversible calmodulin antagonist that inhibits myosin light chain kinase (IC₅₀ = 51 µM) and Ca2+-calmodulin-dependent phosphodiesterase (IC₅₀ = 28 µM).
681635 W-12, Hydrochloride - CAS 89108-46-3 - Calbiochem A cell-permeable and reversible calmodulin antagonist that inhibits myosin light chain kinase (IC₅₀ = 300 µM) and Ca2+-calmodulin-dependent phosphodiesterase (IC₅₀ = 260 µM).
681636-M W-13, Hydrochloride - CAS 88519-57-7 - Calbiochem A cell-permeable and reversible calmodulin antagonist that inhibits myosin light chain kinase (IC₅₀ = 58 µM) and Ca2+-calmodulin-dependent phosphodiesterase (IC₅₀ = 68 µM).
681647 WRN Helicase Inhibitor, NSC 19630 - CAS 72835-26-8 - Calbiochem The WRN Helicase Inhibitor, NSC 19630, also referenced under CAS 72835-26-8, controls the biological activity of WRN Helicase. This small molecule/inhibitor is primarily used for Cell Signaling applications.
684500 Zaprinast - CAS 37762-06-4 - Calbiochem A cell-permeable, selective inhibitor of cGMP-specific phosphodiesterase (PDE V; IC₅₀ = 450 nM).
A1755 Aminophylline ≥98%, powder
SML0846 Anagrelide hydrochloride ≥98% (HPLC)
B3561 BAY 73-6691 ≥98% (HPLC), powder
SML1097 BC8-15 ≥98% (HPLC)
BM0013 BMS-281384 bis-HCl ≥98% (HPLC)
BM0001 BMS-341400 methanesulfonate ≥98% (HPLC)
B8279 4-(3-Butoxy-4-methoxybenzyl)imidazolidin-2-one solid
C0750 Caffeine powder, ReagentPlus®
SML0308 Carbazeran ≥95% (HPLC)
SML0733 Cilomilast ≥95% (HPLC)
C7971 Cilostamide phosphodiesterase inhibitor
C0737 Cilostazol ≥98% (HPLC), powder
SML0366 Cipamfylline ≥98% (HPLC)
PZ0037 Crisaborole ≥98% (HPLC)
D0633 7-(2,3-Dihydroxypropyl)theophylline
D5385 1,7-Dimethylxanthine ~98%, solid
D108 1,3-Dipropyl-7-methylxanthine solid
D9766 Dipyridamole ≥98% (HPLC)
SML1522 Doxofylline ≥98% (HPLC)
E1279 Enoximone solid
E1896 Etazolate hydrochloride solid
F124 Furafylline ≥98% (HPLC)
PZ0172 Gisadenafil besylate salt ≥98% (HPLC)
H9006 7-(β-Hydroxyethyl)theophylline solid
I0157 Ibudilast ≥99% (HPLC), solid
I0782 Imazodan ≥99% (HPLC)
SML1521 Irsogladine maleate ≥98% (HPLC)
I5879 3-Isobutyl-1-methylxanthine ≥99% (HPLC), powder
SML0439 MBCQ ≥98% (HPLC)
M2547 8-Methoxymethyl-3-isobutyl-1-methylxanthine ≥98%
M4659 Milrinone ≥97% (TLC), powder
O7389 Olprinone hydrochloride ≥98% (HPLC), solid
SML1872 ORM-3819 ≥98% (HPLC)
P3510 Papaverine hydrochloride powder
P1784 Pentoxifylline solid
PZ0269 PF-03049423 ≥98% (HPLC)
PZ0349 PF-04449613 ≥98% (HPLC)
PZ0232 PF-04471141 hydrochloride ≥98% (HPLC)
PZ0314 PF-04671536 ≥98% (HPLC)
PZ0251 PF-05180999 ≥98% (HPLC)
PZ0351 PF-2545920 hydrochloride ≥97% (HPLC)
SML0585 Piclamilast ≥98% (HPLC)
SML1333 Pimobendan ≥98% (HPLC)
SML1116 PQ-10 ≥98% (HPLC)
P9689 Propentofylline solid
SML1099 Roflumilast ≥98% (HPLC)
R6520 Rolipram solid, ≥98% (HPLC)
SML0336 Rosavin ≥98% (HPLC)
PZ0003 Sildenafil citrate salt ≥98% (HPLC)
SML1877 Tadalafil ≥98% (HPLC)
SML0910 TC3.6 ≥98% (HPLC)
T4500 Theobromine ≥98.0%
T1633 Theophylline anhydrous, ≥99%, powder
T2057 Trequinsin hydrochloride ≥98%
V6383 Vinpocetine ≥98%, solid
Y4877 YM 976 ≥98% (HPLC)
Z0878 Zaprinast solid
Z3003 Zardaverine phosphodiesterase inhibitor