| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Pharmacology and Therapeutics, Institute of Immunity, Infection, and Inflammation, University of Calgary, Calgary, Alberta, Canada
Correspondence and requests for reprints should be addressed to Mark A. Giembycz, Ph.D., Department of Pharmacology and Therapeutics, Respiratory Research Group, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1 Canada. E-mail: giembycz{at}ucalgary.ca
 |
ABSTRACT |
|---|
 TOP ABSTRACT PDE-4CLINICAL EXPERIENCE WITH PDE4...DUAL-SPECIFICITY PDE INHIBITORSCONCLUSIONSREFERENCES |
|---|
Key Words: cyclic adenosine monophosphate • dual-specificity phosphodiesterase inhibitors • phosphodiesterase-1 • phosphodiesterase-3 • phosphodiesterase-7
Chronic obstructive pulmonary disease (COPD) is a generic term that embraces several debilitating inflammatory pathologies that often coexist, and is characterized by a slowly progressive and largely irreversible decrement in lung function. In particular, persistent airflow limitation, usually associated with airway collapse, edema, and fibrosis, is present to a greater or lesser extent and accounts for the wide spectrum of disease. Thus, individuals with COPD might present with chronic bronchitis as a dominant feature or with emphysema due to destruction and collapse of terminal alveoli. At present, COPD is considered a neutrophilic inflammatory disorder of the lung that is perpetuated, in large part, by macrophages, epithelial cells, and possibly CD8+ T lymphocytes, and is distinct from asthmatic inflammation.
No currently available drug resolves the underlying inflammation in COPD. Although smoking cessation intervention and bronchodilator therapy provide symptomatic relief, there are clear unmet needs for patients with COPD, including effective antiinflammatory therapy and mucolytics, ideally allied with disease-modifying drugs that can repair damaged lung. Since the mid-1990s, there has been considerable interest in the results of preclinical studies, which suggest that inhibition of phosphodiesterase-4 (PDE4) may alleviate the chronic inflammation associated with COPD. Now several selective PDE4 inhibitors, including AWD 12-281, IC-485, ONO-6126, arofylline, GRC 3886, tetomilast, cilomilast, and roflumilast, are in clinical trials of COPD, with the latter two compounds in late phase III development.
|
PDE-4 |
|---|
|
TOPABSTRACTPDE-4CLINICAL EXPERIENCE WITH PDE4...DUAL-SPECIFICITY PDE INHIBITORSCONCLUSIONSREFERENCES |
|---|
|
CLINICAL EXPERIENCE WITH PDE4 INHIBITORS |
|---|
|
TOPABSTRACTPDE-4CLINICAL EXPERIENCE WITH PDE4...DUAL-SPECIFICITY PDE INHIBITORSCONCLUSIONSREFERENCES |
|---|
The improvement in lung function and health status of subjects with COPD given cilomilast in phase II trials prompted additional, 6-mo multicenter phase III studies that involved larger cohorts of patients (Figure 1). In general, cilomilast given to patients with mild to moderate COPD significantly reduced the risk, relative to placebo, of a self-managed exacerbation and of an exacerbation requiring treatment by a physician or hospitalization (3, 4). Equally, in three of these investigations there were statistically significant enhancements in FEV1, FVC, and trough FEV1 (Figure 1). Other lung function parameters, including trough FEF25–75 (forced expiratory flow between 25 and 75% of FVC) and trough FEV6, also were improved by cilomilast, suggesting that a clinically important impact of the drug may have occurred in the small airways (3, 4). Health status and global health status were assessed at baseline and 6 mo after therapy with cilomilast and placebo, using the SGRQ and SF-36, respectively, and yielded results consistent with the data obtained in the phase II study described previously (3, 4).
|
The efficacy of roflumilast also has been reported in placebo-controlled trials involving patients with COPD. Four weeks after treatment, discernible increases in lung function (FEV1, FVC, and morning PEFR) were apparent in the active treatment groups, and the need for rescue medication was reduced (4). Thus, the benefits of PDE4 inhibitors in COPD are not restricted to cilomilast and are likely to be a generic action of these compounds.
Side Effects and Safety Issues
Despite some encouraging data from phase III clinical trials, the current generation of PDE4 inhibitors is hampered by a low therapeutic ratio. Indeed, a major obstacle that became clear in the development of PDE4 inhibitors is their propensity to evoke non–steroid-like side effects, of which nausea, diarrhea, abdominal pain, vomiting, and dyspepsia are the most common, although some of these appear to resolve with continued treatment. The adverse events profile of the current generation of PDE4 inhibitors is a well-recognized part of their pharmacology and is similar to that of first-generation compounds, such as rolipram.
Documentation of toxicities resulting from the administration of PDE4 inhibitors is sparse compared with inhibitors of other cAMP PDE families, such as PDE3. However, there is a worrying potential toxicity, shared by PDE3 inhibitors and other vasodilators, namely arteritis/periarteritis. This condition is characterized by inflammation, hemorrhage, and necrosis of blood vessels, and it is irreversible in animals. Mechanistically, arteritis is thought to result from hemodynamic changes produced by excessive and prolonged vasodilatation of specific vascular beds, although the means by which PDE4 inhibitors cause certain vessels to become targets of inflammation is unknown. In nonhuman primates, studies of PDE4 inhibitors generally have not identified pathological findings, including arteritis, similar to those reported in other species used for toxicology, and this has led to a view that arteriopathies are nonprimate specific. Indeed, rats and dogs may have an increased susceptibility to drug-induced vascular lesions as arteriopathies commonly occur in these species (6, 7). Consistent with this hypothesis, cilomilast is reported not to produce medial necrosis of mesenteric arteries in primates, in contrast to the results of comparable studies performed in rodents (8). However, one comprehensive toxicologic study found that a PDE4 inhibitor, SCH-351591, produced, in cynomolgus monkeys, acute to chronic inflammation of small to medium-sized arteries in many tissues and organs, including kidney, heart, stomach, pancreas, esophagus, mesentery, and gallbladder (9). These findings of arteriopathy in primates, previously thought to be resistant to toxicity, have serious implications for human risk. Indeed, it is noteworthy that Merck Frosst (Montreal, Canada) in 2003 abandoned development of its lead PDE4 inhibitor (licensed from Celltech Group, Slough, Berkshire, UK) because of an occurrence of colitis (10), which might have been secondary to arteritis. Moreover, as COPD is a chronic disease requiring long-term therapy, a wide margin of safety will be needed because toxicity cannot be adequately monitored. The major problem for the physician is that presentation of mesenteric ischemia is vague in humans and diagnostic tools are poor. However, perhaps some comfort can be derived from the knowledge that no clinically relevant effects have been produced in patients treated for many years with bronchodilator doses of theophylline, which produces medial necrosis of mesenteric vessels in rats (11, 12).
Concerns about arteritis have arisen primarily because of the lack of a margin of safety. The U.S. Food and Drug Administration Pulmonary-Allergy Drugs Advisory Committee derives this index from the most relevant animal species, and when evidence of human relevance is lacking, the most sensitive species (usually the rat) is used. In the case of cilomilast, the so-called no observed adverse effect level was achieved in the rat at a fraction of the proposed human dose (13). This is an important point, as a narrow margin of safety often indicates that the drug in question is likely to cause similar effects in humans at the recommended clinical dose.
An additional issue is that in rats, PDE4 inhibitor–induced arteritis is described by a steep dose–response relationship. Using cilomilast as an example, no lesions were seen at a dose of 20 mg/kg, whereas lesions were clearly evident at a dose of 30 mg/kg and higher. At doses of 40 mg/kg and above, cilomilast was lethal (13). Accordingly, the development of arteritis has been identified by the U.S. Food and Drug Administration as a safety issue requiring rigorous monitoring in clinical trials of PDE4 inhibitors (13).
|
DUAL-SPECIFICITY PDE INHIBITORS |
|---|
|
TOPABSTRACTPDE-4CLINICAL EXPERIENCE WITH PDE4...DUAL-SPECIFICITY PDE INHIBITORSCONCLUSIONSREFERENCES |
|---|
PDE3
PDE3 is a cAMP-specific enzyme that is ubiquitously distributed across many cells and tissues (14, 15). Two distinct but related genes have been identified that encode PDE3 isoenzymes, and these have been designated PDE3A and PDE3B (14–17). Interest in PDE3 as a target for the treatment of asthma and COPD stemmed primarily from the finding that selective inhibitors promote bronchodilatation in humans (18–21). Therefore, conceptually, hybrid inhibitors of PDE3 and PDE4 should exhibit both antiinflammatory and bronchodilator activity and so have superior efficacy over compounds that only block PDE4. In addition, inhibition of PDE3 may have desirable effects on the function of certain proinflammatory and immune cells, especially during concurrent PDE4 blockade. In the context of COPD, T lymphocytes, macrophages, monocytes, and endothelial cells, which are rich sources of PDE4, also express PDE3 (1). For example, in vitro studies have shown that whereas PDE3 inhibitors generally have little or no effect themselves on T-cell proliferation or on interleukin (IL)-2 generation, they significantly enhance the effect of PDE4 inhibitors (22, 23). Similar results have been reported for the release of tumor necrosis factor (TNF)-
from human alveolar macrophages (24).
Several dual-specificity inhibitors have been developed and evaluated in humans, including zardaverine, benzafentrine (also known as benafentrine), tolafentrine, and pumafentrine, although there is a dearth of peer-reviewed data from which to gauge the clinical progress of these compounds (25, 26). The compound in most advanced clinical development for both asthma and COPD was pumafentrine (Altana AG, Bad Homburg, Germany). However, development was discontinued in late 2002 as initial phase II trial data did not meet expectations regarding the duration of action. It is implied in the Altana 2003 annual report that the research is now focused on the active metabolite, hydroxypumafentrine, although reference is made only to compounds in preclinical development and so the active metabolite too may also have been abandoned.
Safety issues.
Although the rationale is clear for developing hybrid PDE3/PDE4 inhibitors, there could be major safety concerns with this approach. Selective PDE3 inhibitors were developed in the 1980s as a "safer" alternative to cardiac glycosides for the treatment of dilated cardiomyopathy and, in the short term, beneficial effects on the force of myocardial contraction and on vascular smooth muscle tone were reported. However, for reasons that are still unclear, chronic treatment resulted, paradoxically, in a significant increase in mortality (27). These findings are worrisome, as many individuals with COPD also have right-sided heart failure secondary to pulmonary hypertension (28), and so PDE3/PDE4 inhibitors would presumably be contraindicated in this clinical setting. Moreover, the long-term effect of PDE3/PDE4 inhibitors in individuals with mild COPD in whom cardiac function is normal is unknown.
As mentioned previously, another major cause for concern is arteritis. There is an extensive literature on PDE3 inhibitor–induced arteriopathy in laboratory animals, with the splanchnic vessels and coronary arteries of rats and dogs, respectively, being the most susceptible to lesions (29). Whether clinically meaningful bronchodilatation can ultimately be achieved in humans with an acceptable degree of vasodilatation is largely unexplored, but coincident headache is not uncommon with PDE3 or PDE3/PDE4 inhibitors at bronchodilator doses (21, 30–32). However, the fact that pumafentrine progressed to phase II clinical trials may suggest that systemic exposure and/or cardiovascular activity can be minimized. Conceivably, airway-selective compounds could be realized by optimizing the route of administration (oral vs. inhaled), enhancing clearance from the systemic circulation, reducing bioavailability through plasma protein binding, and/or by exploiting the fact that PDE3 and PDE4 inhibitors interact synergistically to reduce human airway smooth muscle tone (33). Selective targeting of either PDE3A or PDE3B could also offer a more novel approach to reducing cardiovascular toxicity. Indeed, when PDE3 heterogeneity was first appreciated, the terms "cardiac-type" and "adipocyte-type" PDE3 were used to describe what are now known as PDE3A and PDE3B, respectively. This crude taxonomy relied on the finding that PDE3A is expressed primarily in cardiac and vascular myocytes, whereas adipocytes, among other cells, are rich in PDE3B. Furthermore, reverse transcription–polymerase chain reaction analysis using gene-specific primers identified abundant mRNA for PDE3B in human airway smooth muscle (Figure 2A). However, while this differential expression pattern might lead one to hope that the cardiovascular and bronchodilator actions of PDE3 inhibitors are mediated by PDE3A and PDE3B, respectively, the convenient distinction is complicated by the finding that human cardiac myocytes and airway smooth muscle cells express mRNAs for both isoforms (M.A.G., unpublished observations). Moreover, in many cell types where there is coincident gene expression, PDE3A usually predominates (34). Whether PDE3A and PDE3B mediate nonoverlapping, tissue-specific functions in the same tissue is unexplored, although logic dictates that this is highly likely. Thus, it is possible that the cardiovascular actions of PDE3 inhibitors can be dissociated from their effects on airway smooth muscle tone as well as on proinflammatory cell function (e.g., human CD8+ T cells coexpress PDE3A and PDE3B [23]). Subtype-selective compounds, such as vinylogous amide pyrazolones (Figure 2B), are beginning to emerge that could be employed to assess this possibility (35).
|
Heterogeneity of PDE7.
Two genes (PDE7A and PDE7B) have been identified in the mouse, rat, and human that encode PDE7 isoenzymes (36, 39–42). The coding region of HSPDE7A spans 124 kb and contains 14 exons (43). Screening of murine and human skeletal muscle DNA libraries has identified three splice variants (PDE7A1, PDE7A2, and PDE7A3) derived from the same gene. Translation in humans of PDE7A1, PDE7A2, and PDE7A3 mRNA transcripts yields proteins that are composed of 482, 456, and 424 amino acids, respectively. On sodium dodecyl sulfate–polyacrylamide gels, the three splice variants migrate as 55- to 57-kD (7A1), 50- to 52-kD (7A2), and 50-kD (7A3) proteins, masses similar to those predicted from their amino acid compositions (55,506, 52,726, and 48,828 Da, respectively). The amino terminus of PDE7A1 and PDE7A3 is rich in proline, serine, and positively charged amino acids, whereas the same region of PDE7A2 is hydrophobic (38, 44, 45) and features potential myristoylation and palmitoylation sites (at amino acids G2 and C8, respectively) that may dictate intracellular localization. Indeed, after subcellular fractionation of a variety of tissues, PDE7A2 has been found only in the particulate fraction, consistent with the hydrophobicity of its amino terminus; in contrast, PDE7A1 is predominantly cytosolic (38, 44). The subcellular distribution of PDE7A3 has not been investigated, but it shares the same amino terminus as PDE7A1 and could localize to soluble cellular structures.
Distribution of PDE7A in cells relevant to chronic inflammation.
PDE7A and PDE7B are not distributed equally and are thus believed to subserve nonoverlapping, tissue-specific functions. Thus, whereas PDE7A is abundantly expressed in the lung, hematopoietic cells, and placenta, PDE7B is enriched in pancreas, brain, heart, thyroid, and skeletal muscle (39, 40, 46). PDE7B is not present at an appreciable level in cells of the immune system (39, 40, 46) and is not discussed further here. In contrast, PDE7A has been found in many proinflammatory and immune cells (47), implying that these isoenzymes play an important role in regulating many cAMP-dependent processes. Indeed, all human primary cells and cell lines that have been studied express mRNAs for PDE7A1 and PDE7A2 at an approximate ratio of 4:1. However, irrespective of the method used for detection (i.e., Western blotting, immunocytochemistry, and/or confocal microscopy), PDE7A2 has never been found at the protein level, despite unequivocal identification of polymerase chain reaction products corresponding to this transcript. This finding is not peculiar to PDE7A. In human mononuclear cells, several of the PDE4D splice variants are expressed only at the mRNA level (23, 48). No study has explored whether this is due to translational repression or to a low translation rate of these particular mRNA transcripts, instability of the active enzymes, or the fact that the proteins are expressed at low, albeit functional, levels.
Of the immunocompetent/proinflammatory cells that have been studied, CD4+ and CD8+ T lymphocytes express relatively high levels of PDE7A1 that are readily detected by Western blotting (Figure 3A) (47). Human airway smooth muscle cells, blood monocytes, and lung macrophages, together with several cell lines, including HUT-78 (T cell) and BEAS-2B (epithelial), are also PDE7A1 positive under the same experimental conditions (Figure 3A) (47). In contrast, Western blotting has failed to detect PDE7A1 in human neutrophils (Figure 3A), although the protein can clearly be labeled by immunoconfocal laser microscopy (Figure 3B) (47). This more sensitive technique has been employed to determine the expression profile of PDE7A in cells present in sputum and bronchoalveolar lavage fluid. PDE7A is also present in neutrophils recovered from the induced sputum of both normal subjects and individuals with asthma or COPD (47). The lack of immunoreactive bands on Western blots suggests that the concentration of PDE7A in these cells is lower that that found in the other cell types examined. Although immunoconfocal laser microscopy could not distinguish between the PDE7A splice variants, much of the staining is cytosolic, indicating that PDE7A1 may be the most abundant isoform expressed (47).
|
Enzymology of PDE7A.
PDE7A encodes cAMP-specific PDEs that are insensitive (mean inhibitory concentration [IC50] > 100 µM) to cGMP and standard inhibitors of other PDE isoenzyme families (36, 39, 49, 50). The hydrolysis of cAMP by PDE7A1 expressed in yeast (Saccharomyces cerevisiae), bacteria (Escherichia coli), or baculovirus-infected Sf9 (Spodoptera frugiperda) cells follows simple Michaelis–Menten kinetics. The Michaelis–Menten constant, Km (the concentration of substrate that leads to half-maximal enzyme velocity), has been reported to be 10 to 530 nM (36, 38, 44, 49–51).
The hydrolysis of cAMP by PDE7A2 also adheres to simple Michaelis-Menten behavior. However, both the Km (
100 nM) and the Vmax (enzyme velocity at maximal concentrations of substrate) are approximately twofold lower than for PDE7A1 (44). Thus, alternative mRNA splicing has little effect on the kinetics of cAMP hydrolysis catalyzed by PDE7A variants but profoundly influences their subcellular distribution (see HETEROGENEITY OF PDE7). A kinetic analysis of PDE7A3 has not yet been described.
Selective PDE7 inhibitors.
Despite the discovery of PDE7 more than a decade ago, there are surprisingly few reports of selective inhibitors. Data on IC-242 (ICOS Corporation, Bothell, WA) were disclosed. This compound has an IC50 against PDE7A of 370 nM (at 32 nM cAMP) (52) and an isoenzyme selectivity profile similar to that of another selective sulfonamide PDE7 inhibitor, BRL 50481 (Figure 4A), from GlaxoSmithKline (Brentford, Middlesex, UK) (50). In 2004, several series of compounds from Pfizer (New York, NY) and Bristol-Myers Squibb (New York, NY) with PDE7 inhibitory activity were also reported (53–55). One of these, BMS 586353, is a potent (IC50, 8 nM), bioavailable inhibitor of PDE7 with excellent selectivity relative to other PDE isoenzyme families (3722-, 6277-, 1250-, 1231-, and 553-fold less potent against PDE1, PDE3, PDE4, PDE5, and PDE6, respectively [56]). Finally, chemists from Celltech have found that 8-bromo-9–substituted derivatives of guanine are selective inhibitors of PDE7 (57). In particular, incorporation of a bromo-substituted tetralin ring at position 9 of the guanine template results in a compound with an IC50 against PDE7A of 1.3 µM in HUT-78 T cells, with weak activity against PDE3 and PDE4 (14 and 10% inhibition at 10 µM, respectively). Thus, several selective PDE7 inhibitors have now been described that are suitable for in vitro pharmacologic testing.
|
, and TNF-), and production of Th2 cytokines (IL-4, IL-5, and IL-13) evoked by ligation of CD3/CD28 is preserved in T lymphocytes taken from PDE7A knockout mice and from wild-type animals treated with BMS 586353 (56). It is unclear why these results do not concur with data reported by Li and coworkers (58), but it seems unlikely to be species related or a redundant mechanism in mice that compensates for the deficiency in PDE7A. Two additional possibilities may account for the discrepancy. In the study reported by Smith and coworkers (50), CD8+ T lymphocytes were isolated from other leukocytes by negative immunoselection, using a mixture of antibodies against CD11b, CD16, CD19, CD36, CD56, and CD4. Although the same methodology was used by Li and coworkers (58) antibodies against CD25 and HLA-DR were also employed, which remove all activated and proliferating T cells. Thus, it is possible that naive T cells are regulated differently by PDE7A when compared with their activated, proliferating counterparts. Alternatively, the use of naked antisense oligonucleotides by Li and coworkers (58) may not have targeted specifically the mRNA of interest or, alternatively, evoked toxic effects that were sequence nonspecific (65).
Although inhibition of PDE7A with BRL 50481 does not attenuate the proliferation of T cells per se, it significantly augments the antimitogenic and cAMP-elevating activity of rolipram (Figures 4B and 4C) (50). Similarly, the suppression by PDE4 inhibitors of TNF- release from LPS-stimulated human blood monocytes and lung macrophages is significantly enhanced by BRL 50481 (Figure 4D) (50). Collectively, these data are reminiscent of the behavior of PDE3 inhibitors in human T cells (23) and demonstrate that PDE7A can regulate proinflammatory and immune cell function provided that PDE4 is inhibited concomitantly.
Of potential interest is the report by Smith and colleagues in 2004 that culture of human monocytes in RPMI 1640 for 36 h results in upregulation of PDE7A1 and confers functional sensitivity to BRL 50481 (i.e., LPS-induced TNF- release is significantly inhibited) (50). Moreover, in monocytes in which PDE7A1 was upregulated, the inhibition of TNF- release evoked by rolipram and other cAMP-elevating agents was enhanced in a purely additive manner. These data imply that PDE7 inhibitors alone may regulate the responsiveness of monocytes and possibly other proinflammatory and immune cells under circumstances in which PDE7A is highly expressed, such as in chronic inflammation. In this respect, many cytokines relevant to the pathogenesis of chronic inflammatory diseases signal, in part, through a protein kinase C–dependent mechanism (66), and it is known that the human PDE7A1 promoter is activated by phorbol esters (43). Moreover, PDE7A1 expression in human monocytes treated with phorbol myristate acetate is significantly increased relative to time-matched control cells (S. J. Smith and M. A. Giembycz, unpublished observations).
Although inhibition of PDE7A has little or no demonstrable antiinflammatory activity under normal conditions, PDE7A–/– mice respond to immunization (with keyhole limpet hemocyanin) with a significantly enhanced antibody response when compared with wild-type animals (56). Thus, PDE7A may play a central role in cAMP/protein kinase A signaling processes that are unrelated to T-cell activation (56), such as B-cell function.
On balance, the ubiquitous distribution of PDE7A across human immune and proinflammatory cells has provided the impetus to design selective small-molecule inhibitors and to evaluate their potential as novel antiinflammatory drugs. However, of the limited studies thus far reported, inhibitors of PDE7 are remarkably inactive in vitro and in vivo on functional responses that may be considered proinflammatory (e.g., T-cell proliferation and cytokine output). At best, they interact synergistically (normally additively) with PDE4 inhibitors, and in this respect their behavior is reminiscent of that of PDE3 inhibitors in the same experimental settings. Nevertheless, PDE7A may play prominent functional roles under circumstances in which it is upregulated or in responses that have not been empirically investigated, such as antibody production (56). In addition, on the basis of results obtained with BRL 50481, the possibility that greater efficacy could be achieved with hybrid inhibitors of PDE7 and PDE4 is a concept worthy of further investigation and is the focus of several patent filings (67, 68). Still, it should be emphasized that PDE7A mRNA is ubiquitously expressed both peripherally and centrally, so adverse events could compromise the beneficial potential of combined PDE4/PDE7 inhibitors (41, 69, 70).
PDE1
PDE1 is a generic term that describes a family of enzymes that require Ca2+ and calmodulin for activity. In humans, PDE1s are encoded by three genes (PDE1A, PDE1B, and PDE1C), with further complexity arising from differential mRNA splicing. PDE1A and PDE1B preferentially hydrolyze cGMP, whereas PDE1C degrades both cAMP and cGMP with high affinity. Like all other PDE isoenzymes, their expression is regulated both transcriptionally and posttranslationally. In airway smooth muscle from humans and other species, PDE1 accounts for more than 35% of the cyclic nucleotide hydrolytic activity (33), yet its function is unknown.
In 1997, PDE1 was implicated in human vascular smooth muscle proliferation (71, 72), and it is tempting to speculate that one or more PDE1 isoenzymes could subserve the same function in airway myocytes. Rybalkin and colleagues found that PDE1C was markedly induced in proliferating but not quiescent smooth muscle cells derived from human aorta, and, as in human airway myocytes, this enzyme accounted for the major cAMP-metabolizing activity in these cells (71). Subsequently, it was established that induction of PDE1C correlated with cell cycle progression and that mitogenesis was significantly reduced by inhibition of this enzyme with either 8-methoxymethyl-3-isobutyl-1-methylxanthine (a modestly selective PDE1 inhibitor) or antisense oligonucleotides directed against PDE1C (72). As neither zaprinast nor sildenafil (selective PDE5 inhibitors) were antimitogenic in the same system, it was concluded that proliferation due to PDE1C induction involved degradation of cAMP rather than cGMP (72). Collectively, these data indicate that induction of PDE1C lowers cAMP in vascular myocytes, thereby relieving an endogenous "break" and allowing mitogenesis to proceed unhindered. Given that airway remodeling is characteristic of COPD and other airway inflammatory diseases, such as chronic severe asthma (73, 74), dual-specificity inhibitors of PDE1C and PDE4 may selectively target proliferating smooth muscle cells and so retard the remodeling process (PDE1C-mediated) and also arrest inflammation (via PDE4 inhibition). Unfortunately, there are few publications that claim for selective PDE1 inhibitors, although Schering-Plough (Kenilworth, NJ) has identified certain tetracyclic guanines that may be useful pharmacologic tools (75).
|
CONCLUSIONS |
|---|
|
TOPABSTRACTPDE-4CLINICAL EXPERIENCE WITH PDE4...DUAL-SPECIFICITY PDE INHIBITORSCONCLUSIONSREFERENCES |
|---|
|
FOOTNOTES |
|---|
Conflict of Interest Statement: M.A.G. has participated as a speaker in scientific meetings under the sponsorship of GlaxoSmithKline and is a member of the Scientific Advisory Board of Otsuka Pharmaceuticals with relevance to the topic noted in the present article.
(Received in original form April 21, 2005; accepted in final form May 20, 2005)
|
REFERENCES |
|---|
|
TOPABSTRACTPDE-4CLINICAL EXPERIENCE WITH PDE4...DUAL-SPECIFICITY PDE INHIBITORSCONCLUSIONSREFERENCES |
|---|
B and nuclear factor of activated T cells activation. J Pharmacol Exp Ther 2001;299:753–759.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
