Novel pharmacological approaches to the treatment of asthma: status and potential of therapeutic classes Allen J. Duplantier
and Claudia R. Turner
Perhaps the best indicators that contribute
of the diverse mechanisms
to the pathology
of asthma
are the
number and variety of targets that have been identified, largely through advances biology. Here, the authors preliminary
outcomes
that have developed review
is focused
approaches been
in immunology summarize
and molecular the rationale and
for novel therapeutic
approaches
as a result of such advances. primarily
on novel
small-molecule
rather than the improvements
made
development
in existing
asthma
The
therapies
that have or the
of biological agents.
he reasons for the proliferation of therapeutic approaches to the treatment of asthma are numerous. The progress realized in both immunology and molecular biology has made the identification of new drug targets possible. In addition to the ability to pursue new targets, however, there is a more important reason for seeking alternative avenues of asthma therapy. At least 10-15 million people in the USA have asthma, with more than 5,000 asthmarelated deaths reported each yeari. In fact, asthma mortality has increased from 0.8 per 100,000 in 1977 to 2.1 per 100,000 in 1991 (Ref. 2). Not only has the number of asthma-related deaths increased, but hospitalizations, emergency room visits and disease incidence also continue to increases.
T
Several factors may contribute to this trend, including increased exposure to indoor and outdoor allergens4, socioeconomic conditions of minorities that preclude adequate treatments, and the improper use of &agonist&. For these reasons, in the USA, the National Asthma Education Program has recommended that anti-inflammatory agents, such as inhaled steroids, be prescribed as first line therapy for all but the mildest asthmatics because &-agonists only treat symptoms rather than the underlying airway inflammation’. This strategy has led to observed improvements in symptoms and pulmonary function test scoress, but its longterm impact on mortality has yet to be determined. Another issue concerning the currently available therapies may be purely technical. The two major classes of asthma drugs, &-agonists and steroids, are administered as aerosols and this mode of delivery may undermine patient compliance. If so, this necessitates the search for an oral asthma therapy. Neither class is, at this point, amenable to this form of delivery for chronic treatment because of concerns over side-effects. Improvements have been made in currently existing therapies to enhance their efficacy. For example, &-agonists, which are the most potent bronchodilators known, now possess a longer duration of action’. However, they still may not adequately improve the underlying pathogenesis of the disease. Another bronchodilator, theophylline, is now being revisited because it may provide broad spectrum antiinflammatory activity, possibly because of its inhibition of phosphodiesterase (PDE)iO. However, theophylline may
and Claudia R. Turner+, Central ResearchDivision, Pfizer Inc., Groton, CT 06340, USA. *tel: +I 860 441 6009, fax: +I 860 441 5719; +tel: +I 860 441 6097 Allen J. Duplantier*
DDT Vol. 1, No. 5 May
1996
CopyrtghtOElsevler PII:S1359-64461961100181
Science
Ltd. All rights
reserved
1359.6446/96/$15.00
199
Table 1. Leading Class LTD, antagonista
5-LO inhibitorb LTB, antagonista FLAP inhibitorc
leukotriene
antagonists/biosynthesis
Most advanced drug Zafirlukast (ICI 204219) Montelukast (MK 476) Pranlukast (ON0 1078) Zileuton LY 293111 MK 591 BAY-X-l 005
a LTD,, LTB,, leukotriene receptor b 5-LO. 54ipoxygenase CFLAP, 5-lipoxygenase-activating
candidates
in the clinic for the treatment
Company Zeneka Merck ONO/SmithKline Abbott Eli Lilly Merck Bayer
Beecham
of asthma
Status Phase III Phase III Phase III Filed in USA Phase II Phase II Phase II
Ref. 26 27 24 30 29 32 31
subtypes protein
cause side-effects that discourage its use, especially when plasma concentrations exceed 20 &ml; these include tachycardia, headache and nausea”. This observation has spawned the search for selective, oral PDE-IV inhibitors (see below). The anti-inflammatory asthma agents, which include most notably the glucocorticosteroids as well as nedocromil sodium and disodium cromoglycate, also possesspositive and negative attributes. The latter two compounds have poor oral bioavailability and must be administered by aerosol. They appear to be preferentially effective in children, and their use is often limited to mild or moderate asthmaticsi*. Within the steroid classof compounds, some new, highly effective compounds have been developed, including aerosolized fluticasone propionate - a compound that is very potent, requires dosing only twice a day and may have an improved margin of safety13ai4.Even so, inhaled steroid use may still result in voice dysphonia, myopathy of laryngeal muscles,thrush, bone demineralization, oral blood blisters, acne, easy bruising, propellant-induced cough and growth retardation in childrenlsJ6. Thus, ‘soft steroids’ (i.e. steroids that can be metabolized systemically to an inactive form) are being sought in order to overcome this liabilityl7. Although the evolution of these mainstays of asthma therapy is quite interesting and warrants further detail, the intent here is to highlight novel, small-molecule approaches that are being pursued by the pharmaceutical industry to treat asthma. It is in this context that the following molecular targets are described. Leukotriene antagonists and biosynthesis inhibitors The next wave of asthma therapy will include either inhibitors of the 5-lipoxygenase enzyme, or receptor antag-
200
inhibitors
onists of LTD, andLTB,, the products of this metabolic pathway. LTD, causesbronchoconstriction and increasesin vascular permeabilityis. LTB, causes the chemotaxis and activation of neutrophils, eosinophils and mixed T lymphocytes, as well as chemokinesis of monocytesi9. LTB, has also been shown to increase cytokine mRNA and proteinzO and activate natural killer cells and B lymphocytes21. Both LTD, and LTB, induce airway hyper-responsiveness in various animal models22x23. To block the actions of LTD,, several orally delivered LTD, antagonists have been developed (Table l), including zafirlukast (ICI 2042191, montelukast (MK 476) and pranlukast24 (ON0 1078J25.These compounds are primarily bronchodilatory in nature and the former two have demonstrated improvements in the FEV, (forced expiratory volume in 1 s) of 11% (Ref. 26) and 12% (Ref. 27), respectively, in clinical asthma trials. Interestingly, there has also been some suggestion of mild anti-inflammatory activity25. There are also several LTB, antagonists in various stages of development which will most likely be anti-inflammatory in effect28. Eli Lilly evaluated their LTB, antagonist, LY 293111, in atopic asthmatics challenged with antigen. It reduced levels of LTB,, LTC,, LTD,, elastase, myeloperoxidase and interleukin 8 (IL-g), and significantly reduced the number of neutrophils, but had no effect on the number of infiltrating eosinophils and lymphocytes29. Another approach to preventing the actions of these mediators is to block their synthesis by inhibiting 5-lipoxygenase. Of the compounds in this class, zileuton has progressed the farthest, receiving provisional approval from the Pulmonary Advisory Committee prior to dismissalby the FDA for safety reasons. This compound demonstrated a 13.4% increase in FEV, (600 mg, four times daily) in a 4-week trial in mild to moderate asthmatics30.Finally, 5-lipoxygenase
DDT Vol. 1, No. 5 May
1996
IMe
Endothelin
antagonists
Endothelin is a peptide produced by several cell types in the lung, including pulmonary vascular endothelial cells, bronchial epithelial cells, smooth muscle, submucosalglands and type II pneumocytes33. Zafirlukast (ICI 204219) Montelukast (MK 476) There are currently three known forms of endothelin: ET-l, ET-2 and ET-3 F (Ref. 34). ET-l and ET-3 are among the most potent constrictors of human bronchial smooth muscle35336, and this effect is probably Pranlukast (ON0 1078) LY 293111 mediated through the ET, receptor@. In addition to vascular and airway smooth muscle cells, endothelin binding sites are also expressed by fibroblasts, submucosal glands and Zileuton airway nerve@. Endothelin also causes plasma exuOy NHW9-b dation in rats38,increased COOH mucus secretion in feline submucosal gland@, airQfJoUO way smooth muscle hyper\ plasiaa and, possibly, fibroBAY-X-l 005 BAY-Y-1005 blast chemotaxis and mitogenesis*i. These responses Figure 1. Leukotr-iene antagonist/biosynthesis inhibitors. are probably mediated through the ET, recepactivating protein (FLAP) inhibitors have also been identitors33.Endothelin release may be linked to the stimulation fied and evaluated by several companies. Clinical results of airway epithelial cells by a variety of factors, includhave shown that FLAP inhibitors are capable of significantly ing proinflammatory cytokines and endotoxin42A4. Thereimproving FEV, in mild to moderate asthmatics (BAY-X-1005 fore, it is not surprising that increased levels of ET-l and ET-3 12.9% versus 4.8% in placebo131 or asthmatics requiring have been observed in the bronchoalveolar lavage fluid of treatment with inhaled corticosteroids (MK 05916.8% versus symptomatic asthmatics45. Consistent with this observation 0.6% in placebo)3’. is that corticosteroids, which are effective in the treatment of asthma, reduce the secretion of endothelin from cultured Bronchodilators human bronchial epithelial cell@. Different classes and examples of new bronchodilators, Recent advances in the progress of nonpeptide endotogether with the corresponding pharmaceutical companies, thelin antagonists have been reviewed47, and representative are listed in Table 2. structures include L 754142 and PD 156707. Because most of
moETO \ ‘1 ’
DDT Vol. 1, No. 5 May
1996
201
Table 2. New Pharmacological target Endothelin antagonist NOS inhibitorsa Muscarinic antagonist VIP agonistc Potassium channel opener
Tachykinin
antagonist
(NK,)
aNOS, nitric oxide synthase bCOPD, chronic obstructive pulmonary WIP, vasoactive intestinal peptide
bronchodilatina
Representative compounds L 754142 PD 156707 Aminoguanidine .S,S’-[I ,3-Phenylenebis(l,2-ethanediylIbisisothiourea1 Tiotropium bromide Ro-25-1553 BRL 55834 Bimakalim YM 934 SR 48968
Company Merck Parke-Davis
Roche SmithKline Beecham E. Merck Yamanouchi Sanofi
Status Preclinical Preclinical None None Phase III (COPD)b Preclinical Phase II Phase II Phase Ii Phase I
disease
the bronchoconstriction observed in asthma can be explained by leukotrienes and histamine, endothelin antagonists may not prove useful as bronchodilators33. However, the airway remodeling effects of endothelin, such as proliferation of smooth muscle, fibroblast chemotaxis and mutagenesis, and collagen deposition, may be reduced by endothelin antagonists. This may prevent the progressive deterioration of airway function that occurs in asthmatics. Nitric oxide and nitric oxide synthase inhibitors Nitric oxide (NO) is a product of the metabolism of L-arginine catalyzed by NO synthase (NOS), an enzyme that exists in several isoform+@. The inducible Cal+ independent form (iNOS) is regulated at the transcriptional level and is stimulated by such cytokines as tumor necrosis factor (TNF-a, TNF-P), IL-l, interferon-y (IFN-y) and lipopolysaccharide. iNOS is produced by fibroblasts, macrophages, neutrophils and vascular smooth muscle50.The constitutive forms of NOS - eNOS (endothelial) and nNOS (neuronal) are Ca*+/calmodulin-dependent. These forms are stimulated by bradykinin, histamine, acetylcholine, leukotrienes and platelet-activating factor (PAF), and are localized in epithelial cells, endothelial cells, neurons, platelets and neutrophilsso. The human cDNAs encoding the three isoforms of NOS, as well as the structures, chromosomal location and expressional regulation of these isoforms have been reviewedsi. Because NO is a bronchodilator, it was originally thought that asthmatic individuals might suffer from low levels of NO production; however, the converse has proved to be true. Both expired NO, presumably derived from the lower respiratory tracts2, and epithelial NOS are elevated in asthmatic
202
agents
compared to nonasthmatic individual@-55. In addition, upper respiratory tract infections, which may exacerbate asthma, have been associated with elevated expired NO (Ref. 56). Many investigators believe that the amount of expired NO correlates with the degree of airway inflammation Therefore, it is not surprising that inhaled glucocorticosteroids decrease the amount of NO in the expired air of asthmatics5’. These observations may reflect a compensatory mechanism by which asthmatics offset bronchoconstriction in their airways, but the issue is not that simple. As Liggett and coworkers explainjo, if vascular engorgement contributes to asthma pathogenesis, then increased NO may cause bronchial obstruction through its relaxation of vascular smooth muscle. Furthermore, increased NO may result in the enhanced production of toxic metabolites, such as peroxynitrite, that can damage the airway. A more thorough examination of tissue localization of the isoforms of NOS, how NO reaches effector cells, the duration of the NO effect and the metabolism of NO in asthmatics will further clarify the utility of this class of compounds for the treatment of asthma. NO effects are not confined to the lung, and for a useful review of their extrapulmonary activity, see Moncada and HiggG. Most reported NOS inhibitors have been derived from L-arginine. One example, L-NC-nitro-L-argininesg,is selective for the constitutive NOS form, suggesting that ‘the discovery of selective small molecule inhibitors is achievable. Furthermore, the hypertensive side-effects reported for endothelium-derived NO (Ref. 60) provide a good reason why compounds selective for either iNOS or nNOS versus eNOS would be desirable. Subsequent compounds, such
DDT Vol. 1, No. 5 May
1996
as aminoguanidinebl and S,S’-11,3phenylenebis(l,2-ethanediyl)bisisothioureal62, have demonstrated selectivity for iNOS of IO-100-fold (versus eNOS and nNOS) and 190-fold (versus eNOS), respectively. At present, there are no reported NOS inhibitors in the clinic for the treatment of asthma.
0 d’ ‘b
4
L 754142
Tiotropium
PD 156707
bromide
BRL 55634
Bimakalim
OMe
Cl YM 934
SR 48968
Rolipram OMe
OA NH Cl COOH Piclamilast (RP 73401)
SB 207499
CDP 840
1,sNH l-l
HN’ A H2N NH SR 27417
CP 99994
APC 366
Figure 2. Structures of compounds referred to in the text.
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1, No. 5 May
1996
l HCI
Muscarinic antagonists Since the development of the early muscarinic receptor antagonists, five genes, ml through m5iRef. 631, have been cloned and three of these have been associated with three receptor subtypes: M,, M, and M3 (Ref. 64). In an effort to avoid undesirable side-effects associated with nonselective receptor antagonism, including dry mouth, blurred vision and impaired micturitionbs,antagonists that are selective for an individual receptor subtype are being sought. Becauseit is located on effector organssuch assmooth muscleand exocrine glands”, and mediatescontraction of human central and peripheral airway smooth muscle’, the M, receptor subtype has been targeted for obstructive pulmonary diseases.M, antagonistsare potent bronchodilators of cholinergic mediated bronchoconstriction. Their selectivity may enable them to avoid limitations caused by blocking the inhibitory (MJ autoreceptor on the postganglionic cholinergic nerve terminals67. In fact, some M, antagonists have been observed to activate the M, autoreceptor and cause a reduction in acetylcholine
[email protected] role of M, receptors is currently ambiguous. It has been proposed that they facilitate transmission at neural synapses by closing potassium channels, thereby depolarizing postganglionic neurons, but the evidence for this is not entirely clear65. If true, it would explain a bronchodilatory effect of an M, antagonist.
203
Tiotropium bromide, a reported nonselective M, antagonist, is in Phase III for the treatment of chronic obstructive pulmonary disease (COPD). Its use in COPD is being considered not only for its ability to reduce airway obstruction, but also because it may potentially reduce mucus secretier-85. Administered by inhalation as a dry powder at doses of 20-80 kg, tiotropium bromide exhibited significant and sustained protection (32 h) against methacholine challenge@. Given this long duration of action, tiotropium bromide may also be useful for the treatment of nocturnal asthma. For now, however, muscarinic antagonists are seldom used in asthma because of the efficacy of &agonists. Vasoactive intestinal peptide agonists Vasoactive intestinal peptide (VIP) is a neuropeptide that occurs naturally in the airways and other tissue typesTO. Binding of high-affinity receptors in the lung causes a longlasting relaxation of both small and large human airways”. In addition to its ability to relax airway smooth muscle independently of adrenergic receptors, VIP can also prevent bronchoconstriction by a variety of pharmacological agents’*. Furthermore, VIP promotes water and ion transport across the airway epithelium, possibly facilitating the mobilization and elimination of airway secretions. More than 10 years ago a hypothesis was proposed suggesting that asthmatic airways might be deficient in VIP, and that this might underlie airway hyper-responsiveness - a characteristic feature of asthma73. If true, then VIP or a VIP agonist would function as replacement therapy to treat asthma. Thus far, human data have been disappointing, either because VIP itself is rapidly metabolized in the airways or because it does not contribute greatly to bronchorelaxation. Ro-25-1553 is the only VIP antagonist that has been reported in preclinical studies for the treatment of asthma. Ro-25-1553 is a potent, specific and long-acting VIP analog that displays both bronchodilating and anti-inflammatory properties’4. There are currently no clinical data to support the efficacy of this compound, but it is possible that it will perform similarly to VIP itself. If so, this approach may not be useful for the treatment of asthma. If, however, metabolism issues can be avoided, thereby prolonging the bronchodilatory and potential anti-inflammatory effects of this compound, it may be used successfully to treat some of the symptoms of asthma. Potassium channel openers Potassium channel openers (KCOs) are a class of ubiquitous and heterogeneous channels that relax smooth muscle by
204
activating potassium channels in the plasmalemma’5. In the airways, KCOs are effective bronchodilators, and they have also demonstrated the ability to inhibit airway hyper-responsiveness in sensitized guinea pigs76. It has been proposed that this effect may be associated with inhibition at the level of innervation of the airways, possibly through attenuation of nonadrenergic noncholinergic transmission’5. In humans, the KC0 cromokalim reduces night-time wakenings resulting from nocturnal asthma75. However, BRI 38227, the active enantiomer of cromakalim, did not provide any improvement to airway function in asthmatics’6. Furthermore, headache was reported as a major side-effect in the study. These results have spawned the discovery of lung-specific compounds. BRL 55834 is a second generation KC0 with greater selectivity for the lung over the vasculature and is currently in Phase II (Ref. 77). Other KCOs being evaluated in Phase II for the treatment of asthma include bimakalim and YM 934. Tachykinin antagonists In mammalian airways, there is an extensive network of primary afferents of both vagal and spinal origin78. A large proportion of these neurons are unmyelinated C-fibers that contain a class of neuropeptide mediators called tachykinins79. The three predominant mammalian tachykinins are substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), which bind preferentially to NK,, NK, and NK, receptors, respectively80. Tachykinins are released when C-fibers are stimulated by endogenous substances such as eicosanoids81, bradykinin or histamineB*, and may be released after exposure to exogenous agents such as irritant@, pollutant+ and antigenas. Interestingly, exposure to these exogenous substances can induce airway hyper-reactivity in various animal model@ and human+. In in vitro systems, tachykinins can cause smooth muscle contractior+, mucus secretions9 and leukocyte activation9°. In guinea pigs, tachykinin administration induces bronchoconstriction and increased microvascular permeability91. As these endpoints are features of asthmasa, it has been proposed that antagonism of NK,, NK,, or both, may be useful as a therapeutic approach for the treatment of this condition93. SR 48968 is a nonpeptide NK, receptor antagonist in Phase I studies for the acute treatment of asthma. Several companies are also developing NK, antagonists for the treatment of the anti-inflammatory component of asthma. Of these, CP 99994 was examined for its ability to protect
DDT Vol. 1, No. 5 May
1996
Table 3. New Pharmacological PAF” PDE-IV inhibitor+
target
Cytokine inhibitors Chemokine inhibitors IgE modulators Mast cell tryptase inhibitors Adhesion molecules Adenosine A, antagonist
anti-inflammatory
Representative compounds SR 27417 RP 73401 CDP 840 SB 207499 No small molecules reported No small molecules reported No small molecules reported APC 366 No small molecules reported Xanthine analogs patented
agents Company Sanofi Rhone-Poulenc Rorer Celltech/Merck SmithKline Beecham
Status Phase Phase Phase Phase
Arris
Phase II
II II (inhaled) II (discontinued) II
Merck, WO95/11681
aPAF, platelet-activating factor bPDE-IV,
phosphodiesterase
type-IV
against saline-induced bronchoconstriction and cough in asthmatics. It did not significantly prevent either of these responses”*. However, its effects on standard asthma-related endpoints, such as FEV, and symptom scores, are unknown. Anti-inflammatory agents Different classes and examples of new anti-inflammatory agents, together with the corresponding pharmaceutical companies, are listed in Table 3. Platelet-activating factor Platelet-activating factor (PAF) is a potent lipid mediator produced by a variety of human cell types, including neutrophils, alveolar macrophages, eosinophils, mast cells, endothelial cells, monocytes and platele@. Its biological actions are many. PAF induces the chemotaxis, adhesion, activation and degranulation of neutrophils and eosinophils in vitro and in both animal models and humans’s. Furthermore, PAF primes these cell types for greater responsiveness to subsequent stimulation. It also increases the expression of the low-affinity IgE receptor on eosinophils96. PAF administration to the airways of various animal models causes increased microvascular permeability, bronchoconstriction and airway hyper-responsiveness to bronchoconstricting agent@. Because these PAF-induced responses mimic many of those observed in asthmatics, a PAF antagonist seemsto be a reasonable target for pharmacological intervention. Unfortunately, initial efforts by several companies to develop and evaluate PAF antagonists in the clinic were unsuccessful97,98. However, interest in PAF antagonists has been renewed with the demonstration by scientists at Sanofi that their PAF antagonist, SR 27417, blocked the late-phase asthmatic response in human@. If this obser-
DDT Vol. 1, No. 5 May
1996
vation extends to additional asthma-related endpoints, PAF antagonists may follow leukotriene antagonists to the market. PDE-IV inhibitors Phosphodiesterase type-IV (PDE-IV) is a CAMP specific phosphodiesterase with an affinity for CAMP that is 50 times greater than that for cGMP (Ref. 100). Inhibition of PDE-IV prevents the conversion of CAMP to 5’-AMP; consequently, CAMP levels rise. In leukocytes, elevations in CAMP reduce chemotaxis, mediator production and mediator release101~102. In smooth muscle, increased CAMP produces relaxationl03. Given this biological profile, one would expect PDE-IV inhibition to be an effective therapeutic strategy for asthma’“. Prototypical PDE-IV inhibitors such as rolipram are generally associated with emetic side-effects, which limit their therapeutic potentiallo5. For this reason, PDE-IV inhibitors have generally been slow to enter the clinic. However, SB 207499 (Ref. 106) is currently in Phase I clinical trials. Development of CDP 840 was recently discontinued in favor of more potent back-up candidateslo’. If clinical efficacy is observed with these compounds, PDE-IV may prove to be a useful target for asthma therapy, provided that efficacy can be separated from nausea and emesis. An alternative strategy to overcome the side-effect liability is to dose directly into the lung, thus minimizing systemic exposure. Piclamilast (RP 73401), delivered as a dry powder inhaler, is currently in Phase II using this strategy. Cytokine and chemokine inhibitors A range of cytokines have been implicated in the pathogenesis of asthma, most notably, but not exclusively, the Th2
cytokines including IL-4 and IL-5 (Ref. 108). IL-4 promotes immunoglobulin class switching to IgE, the immunoglobulin associated with allergic responsesl”9. IL-4 also promotes mast cell growth and vascular cell adhesion molecule-l (VCAM-1) expressionllOB1ll. IL-5 enhances differentiation and proliferation of T cells, eosinophils and basophilsll*. It also increases eosinophil survival and is chemotactic for eosinophils”3J1*. Furthermore, it can induce the release of histamine and leukotrienes from basophilsll5. There are no known small-molecule antagonists of IL-4. However, a soluble form of the cloned mouse IL-4 receptor is in Phase I trials for asthma (Immunex). Schering Plough is developing an anti-IL-5 compound for the treatment of asthma and allergic disorders, and preclinical results indicate that it blocks migration of eosinophils to the lungs116. Chemokines of interest include RANTES and eotaxin. RANTES is a CC chemokine produced by activated T cells; it induces the migration of memory CD4’ T lymphocytes as well as eosinophilsl17. Eotaxin has been identified recently as a potent eosinophil chemoattractant in guinea pigs, causing the accumulation of eosinophils in both airways and skinl18J19. Because the eosinophil is an important effector cell in asthma and has been identified in the sputum, lavage fluid and in autopsy specimens120, these two chemokines have been receiving much attention. Their identification is so recent, however, that drug discovery efforts have been primarily confined to the biotechnology companies who have cloned and expressed both the ligands and their respective receptors. IgE modulators Although its primary role in host defense is to combat parasitic infections, IgE has also been implicated as the immunoglobulin most closely associated with allergic responses, including inflammation, coughing, bronchoconstriction and mucus secretion’*l. To combat these effects, which plague allergic rhinitic patients as wells as asthmatics, several approaches to IgE modulation are being pursued. Recombinant peptides have been investigated for their potential ability to competitively inhibit the interaction between IgE and its receptor I**. Alternatively, restricting accessibility of the binding site by stabilizing an inactive conformation of IgE or its receptor is another approachl23. Another possibility is to interrupt the interaction between the OLchain of the receptor with its associated subunits so that IgE binds the receptor but signal transduction does not
206
occur121. Once again there are no known antagonists for any of these strategies.
small molecule
Mast cell tryptase inhibitors Efforts to develop mast cell tryptase inhibitors have been made on the strength of experimental data in vitro and from animals models. Tryptase is believed to potentiate the effects of histamineI**, cause the hydrolysis of neuropeptidesl25, cleave C3 to C3a (Ref. 1261, induce eosinophil chemotaxis and activation’*‘, cleave kininogen to form bradykininl28, activate mast cells’27 and function as a growth factor for fibroblasts, epithelial cells and keratinocytes1*‘J29J30. On the basis of these observations, several companies are pursuing inhibitors of mast cell tryptase. In preclinical studies, APC 366 blocked the antigen-induced late-phase response, airway hyper-responsiveness and airway inflammation in sheepl31. Adhesion molecule antagonists The previously mentioned cytokines, IL-4 and IL-5, as well as GM-CSF (granulocyte-macrophage colony-stimulating factor), TNF-a and IL-3, induce the cell surface expression of adhesion molecules such as intercellular adhesion molecule-l (ICAM-1) and VCAM-1 (Ref. 132). These molecules, located on the vascular endothelium, bind integrins located on various inflammatory leukocytes and thus facilitate their diapedesis from the vasculature into organ tissuel32. They may also induce leukocyte activation and leukocyte-interstitial cell interactions, all of which may contribute to the underlying pathology of asthmal32. In fact, endothelial expression of both ICAMand VCAM-1 is increased in asthmatic@. Thus, efforts to block the integrin-adhesion molecule interaction have begun in hopes of developing pharmacological agents that block this component of the inflammatory response. Although many companies are working in this area, there are no reported small-molecule adhesion molecule antagonists in clinical trials for the treatment of asthma. Adenosine A, antagonists Recent observations suggest that adenosine may also play a role in the pathogenesis of asthma. Adenosine can cause bronchoconstriction when inhaled by asthmatics, possibly by stimulating the release of mast cell-derived mediators, such as histamine and leukotrienesl343135. Interestingly, it does not cause bronchoconstriction in nonasthmatic subjects, suggesting that adenosine is an indicator of
DDT Vol. 1, No. 5 May
1996
nonspecific airway hyper-responsiveness in asthmaticsl36. The role of adenosine in asthma is further supported by its increased levels in the lavage fluid of asthmatics compared to normal individualsl37. Three adenosine receptors have been identified and cloned: A,, Aza, A,, and A, (Ref. 138). A, is located on mast cell@ and, since mast cells play an important role in immediate hypersensitivity reactions, A, is of interest as a potential target for the treatment of asthma.
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*The anti-inflammatory effect of any compound must at least equal that of inhaled steroids. *If delivered as an aerosol, a compound must avoid the side-effects observed with steroids and have a faster onset of action. *An effective, orally administered anti-inflammatory agent could conceivably improve patient compliance and, if so, might demonstrate a clear advantage over inhaled steroids.
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Conclusions This review has highlighted the major rationales and preliminary outcomes for new small-molecule agents in asthma therapy; it is not intended to be exhaustive. At this point, there is evidence that leukotriene antagonists or biosynthesis inhibitors are useful in the treatment of asthma, either in their own right or as a means to decrease a patient’s reliance on inhaled steroids and &-agonists. The PDE-IV inhibitors may prove to be useful anti-inflammatory agents if gastrointestinal and CNS-related side-effects can be avoided. The lack of efficacy of early PAF antagonists was a great disappointment, but newer compounds with greater potency and, perhaps, more relevant receptor antagonism may yet prove useful in asthma therapy. With regard to the tachykinin antagonists, it will be interesting to see whether a therapeutic effect can be achieved with antagonism of only one receptor subtype or if both NK, and NK, must be blocked. Other approaches are in their infancy, and it is too early to know whether they are serious contenders or not. Several things are quite clear, however. Simple bronchodilation is an unrealistic rationale for a new therapy because the P,-agonists are not only extremely potent, but also long-acting in their newer versions. Furthermore, trends in medical practices are to reduce the use of &agonists to an ‘as-needed’ basis only, not for scheduled therapy. Of the anti-inflammatory approaches, there are three major considerations:
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