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