Discovery of a First-in-Class Drug, a Prostaglandin D₂ Antagonist, for the Treatment of Allergic Diseases

Abstract

Prostaglandin D₂ (PGD₂) is a major lipid mediator produced by mast cells in response to IgE-dependent stimuli. In patients with allergic diseases such as allergic rhinitis and asthma, the level of PGD₂ is known to increase in nasal and bronchial lavage fluids after allergen challenge. Although PGD₂ has been reported to exert a variety of inflammatory effects such as increases in nasal airway resistance and vascular permeability and eosinophil infiltration, there are few reports on the efficacy of PGD₂ receptor (DP1) antagonists, either in subjects with allergic diseases or in animal models. In 1994 we started a PGD₂ project to discover DP1 antagonists for the treatment of allergic diseases and. by carrying out structure-activity relationship studies, we eventually established S-5751 as a candidate first-in-class drug. In vivo pharmacology studies demonstrated that it dramatically inhibited antigen-induced nasal congestion and inflammatory cell migration in allergic rhinitis models as well as dramatically suppressing bronchial hyper-responsiveness and lung inflammation in asthma models. In 2000, the world’s first phase 2 clinical study with a DP1 antagonist was carried out in patients with allergic rhinitis. However, no significant efficacy was shown, although some favorable findings were seen in a subanalysis. Based on pharmacokinetics (PK)/pharmacodynamics (PD) analysis in the human subjects and animals used for pharmacology studies, we speculated that the failure of the phase 2 study was due to insufficient exposure in humans compared to animal models rather than being due to a minor role of PGD₂ in the pathogenesis of allergic diseases. Subsequently, a structure-activity relationship study was conducted again, using alternative lead compounds and in 2007 we found a back-up compound. S-555739, in which the PK profile and DP1 antagonistic activity was markedly improved. Phase 1 studies have demonstrated that S-555739 is well tolerated and shows a good PK profile with once-a-day dosing, and now a phase 2 study is being planned. Using S-555739, not only the potential of a DP1 antagonist as a first-in-class drug in the treatment of allergic diseases but also the role of PGD₂ in the pathogenesis of allergic diseases will be clarified.