Pharmacology of PDE family specific inhibitors
| PDE | Inhibitors | Source | IC50 | Reference | Usage |
|---|---|---|---|---|---|
| PDE1 | Vinpocetine IC224 SCH51866 | W-A ICOS Schering | 14 μM 80 nM 13–100 nM | Hagiwara et al. (1984) Snyder et al. (2005) Watkins et al. (1995) | Only recently have selective PDE1 inhibitors been developed; IC224 may be the most selective in intact cells |
| PDE2 | EHNA BAY 60-7550 PDP IC933 | W-A Bayer Bayer ICOS | 1 μM 4.7 nM 0.6 nM 4 nM | Podzuweit et al. (1995) Boess et al. (2004) Seybold et al. (2005) Snyder et al. (2005) | Inhibitors are being investigated for improving memory and decreasing endothelial permeability under inflammatory conditions |
| PDE3 | Cilostamide Milrinone Trequinsin Cilastazol OPC-33540 | W-A W-A W-A Otsuka Otsuka | 20 nM 150 nM 300 pM 200 nM 0.3–1.5 nM | Hidaka et al. (1979) Harrison et al. (1986) Ruppert and Weithmann (1982) Tanaka et al. (1988) Sudo et al. (2000) | Milrinone is a currently approved treatment for short term congestive heart failure; cilastazol is a treatment for intermittent claudication |
| PDE4 | Rolipram Roflumilast Cilomilat Ro 20-1724 AWD 12-281 SCH351591 V-11294A | W-A Altana GlaxoSmithKline W-A Elbion A-G Schering Purdue Frederick | 1 μM 0.8 nM 120 nM 2 μM 9.7 nM 58 nM 405 nM | Schwabe et al. (1976) Hatzelmann and Schudt (2001) Barnette et al. (1998) Sheppard and Tsien (1975) Schmidt et al. (2000) Billah et al. (2002) Gale et al. (2002) | Multiple compounds have undergone trials for treatment of chronic obstructive pulmonary disease but have experienced limited success because of side effects; compounds are also under investigation for several other inflammatory conditions; interest exists in using PDE4 inhibitors for CNS disorders, including depression and improvement of memory |
| PDE5 | Zaprinast Sildenafil Vardenafil Tadalafil DA-8159 | W-A Pfizer Bayer Lilly-ICOS Dong-A | 0.13 μM 10 nM 1 nM 10 nM 6 nM | Lugnier et al. (1986) Boolell et al. (1996) Bischoff et al. (2001) Padma-Nathan et al (2001) Oh et al. (2000) | Sildenafil, vardenafil, and tadalafil are in usage as erectile dysfunction drugs; these compounds are in trials for other indications such as pulmonary hypertension and benign prostatic hyperplasia |
| PDE6 | Inhibition of PDE6 may be a source of sildenafil side effects on vision; genetic mutations in PDE6 are the basis for several vision related diseases, but PDE6 has not been investigated as a therapeutic target | ||||
| PDE7 | BRL 50481 IC242 | GSK ICOS | 260 nM 370 nM | Smith et al. (2004) Lee et al. (2002) | PDE7-selective inhibitors have been investigated as anti-inflammatory agents in vitro but so far have shown limited utility in vivo |
| PDE8 | No truly selective inhibitors are yet available | ||||
| PDE9 | BAY 73-6691 | Bayer | 55 nM | Wunder et al. (2005) | BAY 73-6691 is in preclinical development for Alzheimer's disease treatment |
| PDE10 | No truly selective inhibitors are yet available | ||||
| PDE11 | PDE11 has received pharmacological interest because it is also inhibited by tadalafil and thus is a potential source for side effects |
W-A, widely available; SCH51866, (+)-cis-5,6a,7,8,9,9a-hexahydro-2-[4-[trifluro-methyl] phenylmethyl]-5-methyl-cylopent[4,5]imidazo[2,1-b]purin-4(3H)one; EHNA, erythro-9-(2-hydroxy-3-nonyl)adenine; PDP, 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one; Ro 20-1724, 4-[(3-butoxy-4-methoxyphenyl)-methyl]-2-imidazolidinone; AWD 12-281; N-(3,5-dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide; SCH351591, 3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)-quinoline-5-ylcarboxamido]pyridine-1-oxide; V-11294A, 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine hydrochloride; DA-8159, 5-[2-propyloxy-5-(1-methyl-2-pyrollidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidine-7-one