Prostaglandin D2 (PGD2) belongs to a class of chemical mediators which cells synthesize in response to stimuli, such as local tissue damage or hormonal stimuli, or by cellular activation pathways. Cells synthesize PGD2 from arachidonic acid by cyclooxygenase and other specific synthases in the pathway.
Upon stimulation, mast cells release PGD2 in major amounts and this release plays a major role in the etiology of respiratory disease, such as asthma and congestion. PGD2 achieves this effect by binding with either of two G-protein coupled receptors, which are the D-prostanoid (DP) receptor and the CRTH2 receptor. TH-2 cells, eosinophils, and basophils express the CRTH2 receptor, which mediates the chemoattractant effect of PGD2.
Scientific studies support a clear role for PGD2 in an allergic inflammatory response. PGD2 is found at high levels in the bronchioalveolar lavage of asthmatics. Inhalation of PGD2 enhances eosinophilic and lymphocytic airway inflammation in allergic animal models. Evidence obtained by studying CRTH2 knockout mice demonstrates that PGD2 achieves this enhancement by binding to the CRTH2 receptor. Hence, CRTH2 receptor antagonists would be expected to reduce the allergic inflammatory response caused by PGD2, and these compounds would be useful in the treatment or prevention of allergic/immune disorders.
Current drugs of choice for the treatment of chronic inflammatory airway disease, such as asthma or COPD, are synthetic glucocorticoids; examples of these compounds currently indicated for treating these disorders include fluticasone and mometasone. The difficulty with treating patients with this class of compounds is that the compounds possess a number of systemic side-effects; these include adrenal suppression, altered bone metabolism and growth suppression in children. These side effects limit the dose that can be administered on a daily basis to the patient. While a non-steroidal class of therapeutics that inhibit bronchoconstriction exists (CysLT1 antagonists), this class of compounds has limited efficacy in achieving the endpoints of reducing inflammatory and improving in lung function when compared to the glucocorticoids. Therefore, a therapeutic that combines the efficacy of inhaled glucocorticoids without the side effects would be advantageous.
USPTO Backgrounds
USPTO Backgrounds