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Development Of Human Hematopoietic Prostaglandin D2 Synthase Inhibitors For Allergic Asthma

Mark Smythe, Institute for Molecular Bioscience, The University of Queensland
Christina Kulis, Institute for Molecular Bioscience, The University of Queensland

Asthma is one of the most common chronic respiratory diseases in developed countries.  Asthma accounts for about one out of every 250 deaths worldwide and has profound health-care costs in terms of emergency room visits and hospitalisations.1 Within Australia there was an estimated 4 million people with asthma in 2008.2 There were 449 deaths due to Asthma (2 per 100,000 people) in Australia in 2008 (Australian Bureau of Statistics, 2010).

Most patients with asthma effectively control the disease with the combined use of corticosteroids and long acting beta agonists, anti-cholinergics and leukotriene receptor agonists. However, approximately 10% of patients fail to respond to conventional therapies due to severe and/or steroid refractory disease, these patients account for more than 50% of the total healthcare costs of asthma.

In patients with severe asthma there is a coordinated up-regulation of the Prostaglandin D2 (PGD2) pathway, including the hematopoietic prostaglandin D2 synthase (HPGD2S) enzyme, the product of this enzyme (PGD2) and one of the receptors for PGD2 (CRTH2).3 In addition PGD2 is readily detected in nasal and bronchial lavage fluids4 of patients with asthma, atopic dermatitis and allergic conjunctivitis, and is upregulated upon allergen exposure.5 In asthmatics, PGD2 modulates the physiology of the airways by causing bronchoconstriction,6 vasodilation,7 increased capillary permeability,8 mucous production,9 and inflammatory cell invasion.10 It promotes nasal congestion and fluid secretion in humans, more so than other allergic mediators.11,12  HPGD2S is responsible for overproduction of PGD2 in tissues and cell types predominantly associated with these inflammatory conditions including lung and activated mast cells, and is a well validated drug target for treatment of asthma and allergic rhinitis. Blockade of PGD2 action by modulation of its synthesis will provide a new approach to disease management.

Funded by Therapeutic Innovation Australia and NHMRC Development grant, we have developed potent and specific inhibitors of HPGD2S that that are orally bioavailable, metabolically stable and efficacious in vivo. Key compounds are currently being selected for further investigation in disease models of asthma.

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