There is a pressing need to develop new treatments for the chronic obstructive pulmonary diseases (COPD), chronic obstructive bronchitis and emphysema. World-wide, 600 million people suffer from COPD, with some three million dying from the disease each year. This serious healthcare problem is paralleled by a global market of US$2.8 billion. There is a particular need to develop drugs that control the underlying inflammatory and destructive processes that cause COPD as no currently available drug therapy reduces the relentless progression of COPD. In contrast to the enormous advances made in asthma management little significant progress has been made in COPD therapeutics.

In our recent analysis of COPD, produced in collaboration with field-leader Peter Barnes, we highlight the clinical needs and pharmaceutical development surrounding COPD and review emerging pharmaceutical targets (click here for dossier access). One target addressed was that of the protease inhibitors. There is compelling evidence for an imbalance between proteases that digest elastin (and other structural proteins) and antiproteases that protect against this. This suggests that either inhibiting these proteolytic enzymes or increasing endogenous antiproteases may be beneficial and theoretically should prevent the progression of airflow obstruction in COPD. Small molecule inhibitors, such as ONO-5046, have been developed which are high potency protease inhibitors and which are able to inhibit neutrophil elastase-induced lung injury in experimental animals. While such treatments would be expected to slow disease progression few strategies have been identified that may reverse airway damage. The target that has received the greatest attention in this respect is the retinoic acid receptor.

We have analyzed the therapeutic and pharmaceutical potential of the retinoids in a recent DiscoveryDossier (Click here to access). With respect to COPD, retinoic acid increases the number of alveoli in developing rats and, remarkably, reverses the histological and physiological changes induced by elastase treatment of adult rats. As well as showing promise as a curative treatment, the retinoids may also block the activity of certain molecules that contribute to disease progression. A very early publication reported that retinoic acid was able to reduce elastase activity while later studies reported the ability of retinoic acid to down-regulate matrix metalloproteinase-9 and up-regulates tissue inhibitor of metalloproteinase-1. More recently Japanese researchers have shown that retinoic acid prevented the ability of elastase to reduce the viability of human airway cells. The pro-apoptotic effect of elastase was also reduced. Retinoic acid may, therefore, have both protective and curative effects in the context of COPD. Despite the considerable potential of the retinoids little development activity has been reported with respect to COPD.

Entry date March, 2003

Adapted from Nakajoh et al, Am J Respir Cell Mol Biol 2003 Mar;28(3):296-304 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk