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.