The development of a dual 5-LO inhibitor/H1 receptor antagonist for the treatment of asthma
SummaryNumerous inflammatory mediators have been implicated in the etiology of asthma. Blocking specific inflammatory mediators has frequently yielded unimpressive clinical results and instead the simultaneous targeting or more than one mediator may be of greater use. In the current edition of LeadDiscovery's TherapeuticAdvances work by researchers at UCB who have developed a dual 5-LO inhibitor/H1 receptor antagonist is highlighted
The incidence of asthma has dramatically increased over recent years and although currently available treatments are generally effective, patient compliance is currently poor, especially with respect to inhaled treatment. Furthermore, 5% of patients are unresponsive to these treatments and it is this cohort that accounts for a large segment of asthma related healthcare cost.
The lack of effective oral therapies means that inhalation will remain the primary mode of delivery in the medium term. In our recent feature "Asthma and COPD - Combinations breathe life into the asthma and COPD markets" it is predicted that the market for airway inflammatory diseases will increase by 35% to over $18 billion by 2011, largely driven by the success of combined steroid/beta agonist formulations, rather than novel drug launches (click here for this report). More distant advances are however likely to focus on novel anti-inflammatory targets.
In LeadDiscovery's recent DiscoveryDossier "Asthma Therapeutics: New treatment options and emerging drug discovery targets" produced in collaboration with field leader Peter Barnes, we evaluate those anti-inflammatory targets receiving greatest attention. Amongst the first wave of new anti-inflammatory therapeutics were leukotriene receptor antagonists and inhibitors of 5-lipoxygenase (5-LO), an enzyme key to the production of the leukotrienes. These drugs have attracted considerable attention being the first new class of treatment for asthma in over 30 years.
Leukotriene (LT) D4 is one of the several peptidoleukotrienes, which are potent, pro-inflammatory agents responsible in part for bronchoconstriction during an asthmatic attack. Despite the pro-inflammatory effects of LTD4, receptor antagonists such as montelukast, pranlukast and zafirlukast are considerably less effective at treating asthma and more expensive than inhaled corticosteroids. Asthma is a complex respiratory disease involving some 50 mediators and the limited efficacy of the leukotriene receptor antagonists supports the concept that targeting more than one of these mediators may improve the clinical benefit.
5-LO is responsible for the synthesis of LTD4 as well as LTB4 with the latter playing a role in asthma, particularly in more severe asthma and in exacerbations where neutrophilic inflammation may become more prominent. Hence the development of 5-LO inhibitors was considered to represent an improvement over the receptor antagonists. Zileuton, one of the prototypic 5-LO inhibitors, is a relatively poor inhibitor. However, in terms of clinical efficacy, it is similar to the more potent leukotriene receptor antagonists.
Like the leukotrienes, histamine has a number of pro-inflammatory effects and as such this mediator could contribute to various aspects of asthma etiology. Despite this, antihistiminergic drugs have been found to be of little use in the clinic once again reflecting the role of multiple mediators. Consistent with this, clinical data in asthmatics demonstrate that those patients treated with a combination of an LTD4 receptor antagonist (zafirlukast) and a histamine H1 receptor antagonist (loratadine) responded better than those patients treated with a single drug. Similarly, the combination of montelukast (LTD4 receptor antagonist) and cetirizine (H1 receptor antagonist) has proven equally effective as corticosteroids for asthmatics.
In their recent study, researchers from UCB have built upon these findings by developing a dual 5-LO inhibitor/H1 receptor antagonist. To do this Lewis et al combined the pharmacophore of these two classes. Specifically they combined the ring-butynylhydroxyurea pharmacophore of the 5-LO inhibitors, ABT-761 and CMI-977, with the benzhydryl piperazine pharmacophore of the H1 antagonists cetirizine and efletirizine. A series of "dual-function" candidates was thus synthesized and then screened in classic H1 and 5-LO assays. One molecule in this series inhibited 5-LO with a greater potency than that of zileuton and antagonized H1 receptor binding with only a 10-fold lower potency than that of cetirizine. Given the acceptable pharmacokinetic profile of this candidate it was then evaluated in vivo and was shown to inhibit histamine-induced bronchoconstriction to a similar degree as cetirizine albeit at a 4-fold lower dose. Likewise, oral dosing also reduced 5-LO activity as determined ex vivo to a similar extent as zileuton.
The strategy adopted by Lewis et al has therefore led to the development of a balanced dual 5-LO inhibitor/H1 receptor antagonist with oral activity. Given the clinical findings that the simultaneous inhibition of leukotriene function and antagonism of the H1 receptor is of benefit to asthma patients, the further development of the UCB molecules through models of asthma and into the clinic is eagerly awaited. (source LeadDiscovery TherapeuticAdvances)
Adapted from Lewis et al, Bioorg Med Chem Lett. 2004 May 3;14(9):2265-8