Activation of the chemoattractant receptor-homologous molecule expressed on T helper-2 cells (CRTH2, also known as DP2) by prostaglandin D2 (PGD2) induces pro-inflammatory responses. Development of CRTH2 receptor antagonists could therefore be useful to treat allergic and type 2 inflammatory diseases such as allergic rhinitis, atopic dermatitis, asthma, or nasal polyposis [1].

We previously reported the discovery of setipiprant which was in advanced clinical development [2]. Late stage clinical studies with setipiprant in seasonal allergic rhinitis (Phase 3) [3] did not confirm efficacy findings made in earlier studies. Our efforts to identify a more potent backup compound started by modifying the core of the molecule and synthesizing tetrahydrocarbazole derivatives with drug-like properties. Further lead optimization guided also by in-vitro cytotoxicity profiling finally led to the discovery of the clinical candidate ACT-774312, which is currently in Phase 2 development in nasal polyposis [4].

In this presentation, we will describe our medicinal chemistry efforts that culminated with the identification of ACT-774312 [5].

[1] R. Pettipher et al., Nat. Rev. Drug Disc., 2007, 6, 313-325.
[2] H. Fretz et al., J. Med. Chem., 2013, 56, 4899-4911.
[3] P. Ratner et al., Allergy Asthma Clin. Immunol., 2017, 13:18.
[4] M. Géhin et al., Basic Clin. Pharmacol. Toxicol., 2019, 124, 711-721.
[5] H. Aissaoui et al., Manuscript in preparation.