ReviewImmunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors
Introduction
It has been approximately a decade since early studies Crummey et al., 1987, Torphy and Undem, 1991 first highlighted the anti-inflammatory and smooth muscle relaxant effects of cyclic AMP phosphodiesterase (PDE) 4 inhibitors that suggested their potential in the treatment of asthma. During the intervening period, many pharmaceutical companies have embarked on programs of work to identify their own PDE4 inhibitors, not only for the treatment of asthma, but also other chronic inflammatory diseases such as arthritis, chronic obstructive pulmonary disease (COPD), atopic dermatitis and multiple sclerosis (MS). At the time of writing (mid-1999), over 450 patents have been published and several compounds have been evaluated in the clinic, mostly for asthma. However, in general, the clinical results to date with PDE4 inhibitors in asthma have been disappointing and several development compounds have been discontinued. As well as this intensive activity on the pharmaceutical front, the last 10 years have witnessed great leaps forward in our understanding of the molecular biology and biochemistry of PDE4 as well as the pharmacology of PDE4 inhibitors, which may create opportunities for future therapeutic innovations.
The current article briefly reviews the molecular biology and biochemistry of PDE4 as well as the in vitro and in vivo data supporting the view that PDE4 inhibitors are potentially exciting novel drugs for the treatment of chronic inflammatory diseases. The reasons for the failure of PDE4 inhibitors in the clinic are addressed and the possibility that advances at the molecular level will translate into the identification of PDE4 inhibitors with greater therapeutic success is critically discussed.
Section snippets
Cyclic AMP cascade
Cyclic AMP is a ubiquitous second messenger that transduces intracellular signals initiated by many biologically active agents exerting their effects through activation of adenylyl cyclase. It plays an important role in the immune system, exerting generally suppressive effects on the functions of inflammatory and immunocompetent cells (Kammer, 1988). The only known way in which cyclic AMP exerts its biological actions is through binding to the regulatory subunit (R) of the heterodimeric cyclic
PDE isoenzyme family
Cyclic nucleotide PDEs (EC 3.1.4.17), discovered more than 30 years ago (Butcher and Sutherland, 1962), hydrolyse the phosphodiester bond of purine cyclic nucleotides (cyclic AMP, cyclic GMP) to their corresponding 5′-mononucleotides (5′-AMP, 5′-GMP), which do not activate cyclic nucleotide-dependent protein kinases. Multiple PDEs have been identified (Beavo et al., 1994). These isoenzymes differ in their substrate specificity, kinetic properties, responsiveness to endogenous regulators (Ca2+
Multiple PDE4 forms
Four human and rat PDE4 genes (PDE4A, B, C, D) have been identified and their locations on human and mouse chromosomes determined (Houslay et al., 1998) (Table 2, Fig. 1). Multiple splice variants exist for at least three of the four PDE4 genes (Houslay et al., 1998). The conservation of many individual mRNAs between human and rat demonstrates PDE4 to be a highly conserved multigene family. Sequence analysis has identified several highly conserved domains in PDE4 subtypes. The catalytic domain,
PDE4 inhibitor structural types
As shown in Fig. 2, over 450 PDE4 inhibitor patents have been published during the past 10 years, reflecting the huge interest in the therapeutic potential of this class of compounds. Most of the chemistry has been based on rolipram although xanthines (e.g. denbufylline, arofylline), nitroquazone and quinoline/napthaline (e.g. T-440) analogues have been widely evaluated in pre-clinical models Palfreyman and Souness, 1996, Norman, 1998. Clinical data, mostly in asthma, have been reported on
Anti-inflammatory effects of PDE4 inhibitors in vitro
PDE4 is widely distributed in cell types implicated in chronic inflammatory diseases such as asthma (Table 3). Its physiological importance is demonstrated by the wide-ranging suppression of many inflammatory/immunocompetent cell functional responses by PDE4 inhibitors (Table 4).
Potential of PDE4 inhibitors in chronic obstructive pulmonary disease (COPD)
While most pharmaceutical companies in the PDE4 field have targeted asthma, recent clinical results with the SmithKline-Beecham compound, Ariflo, suggest considerable potential for PDE4 inhibitors in the treatment of COPD. This section presents the preclinical data suggesting potential of PDE4 inhibitors in airways inflammatory diseases and clinical data in asthmatic and COPD patients. Although the potential utility of PDE4 inhibitors in treating these airway disorders is due to their direct
Potential of PDE4 inhibitors in arthritis
RA is a painful, crippling systemic autoimmune disease of uncertain cause characterized by inflammation and progressive destruction of synovial joints (Pincus and Callahan, 1993). T-cells and monocytes, which are abundant in the RA synovium, play an important role in the disease. IL-1β and TNF-α are believed to play pivotal roles in causing the tissue damage in the RA joint and, in experimental models, administration of TNF-α directly into the rheumatoid joint initiates synovitis directly
Potential of PDE4 inhibitors in MS
Because of the numerous reports indicating that PDE4 participates in the biochemical processes controlling the behaviour of mammals and lower organisms, the potential of PDE4 inhibitors in treating various psychotic disorders was identified and early compounds such as rolipram and denbufylline were developed for diseases such as depression and dementia (Palfreyman and Souness, 1996). Indeed, rolipram is still being developed by Meiji Seika in Japan for post-shock depression (Norman, 1998). More
Potential of PDE4 inhibitors in dermatological disorders
Although the level of interest in PDE4 inhibitors as potential treatments for dermatological disorders has fallen a long way short of that directed at respiratory disorders, compounds have been evaluated with some success in patients with dermatological complaints such as atopic dermatitis (AD) and psoriasis Sawiski et al., 1979, Hanifin, 1991, Hanifin et al., 1996. AD is a chronic inflammatory skin disease characterized by pruritis, cutaneous reactivity and erythma, frequently seen in patients
Potential of PDE4 inhibitors in other inflammatory diseases
A glance through the numerous patents on PDE4 inhibitors reveals a large number of indications for which this class of compounds is claimed to be of therapeutic benefit. Many of these are diseases in which TNF-α is implicated as an important pathological factor. In general, there is little hard, published data in experimental animal models to support most of these claims. However, several studies in animal models have demonstrated that PDE4 inhibitors suppress inflammation in a variety of
Side-effects and strategies to improve therapeutic ratios
From the previous discussion, it is clear that PDE4 inhibitors have considerable therapeutic potential. Furthermore, they are generally devoid of the cardiovascular side-effects (increased cardiac contractility, vasodilatation, potential arrhythmogenic activity) associated with PDE3 inhibitors (Treese and Rhein, 1990). However, they do exhibit a number of side-effects which may limit their potential therapeutic utility, especially if they are to be administered by mouth. This, perhaps, is not
Conclusions
Ten years have passed since the publication of the first information highlighting the potential of PDE4 inhibitors for the treatment of asthma, and where do we stand? A large number of structurally diverse compounds have been synthesised and, although many show impressive efficacy in preclinical models, results in asthma patients to date have been disappointing. Arofylline, CDP-840 and Ariflo and others that have been evaluated orally and all, with the exception of Ariflo, have exhibited
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