Design, Synthesis, and Optimization of Indole Acetic Acid Derivatives as Potent and Selective CRTH2 Receptor Antagonists: Discovery of ACT‐774312

Herein we report the structure‐activity relationship (SAR) studies and optimization of new highly potent and selective CRTH2 receptor antagonists as potential follow‐ups of our previous reported clinical candidate setipiprant (ACT‐129968) for the treatment of respiratory diseases. Structural modification of the amide part of setipiprant (ACT‐129968) led to the identification of the tetrahydrocarbazole derivative (S)‐B‐1 (ACT‐453859) ((S)‐2‐(3‐((5‐chloropyrimidin‐2‐yl)(methyl)amino)‐6‐fluoro‐1,2,3,4‐tetrahydro‐9H‐carbazol‐9‐yl)acetic acid). This compound which displayed a substantial improvement in potency in the presence of plasma versus setipiprant (ACT‐129968) has exhibited an excellent overall pharmacokinetic profile. Further lead optimization to overcome a safety issue as observed in non‐clinical studies with (S)‐B‐1 (ACT‐453859), led to the discovery of the 4‐azaindole derivative (S)‐72 (ACT‐774312) ((S)‐2‐(8‐((5‐chloropyrimidin‐2‐yl)(methyl)amino)‐2‐fluoro‐6,7,8,9‐tetrahydro‐5H‐pyrido[3,2‐b]indol‐5‐yl)acetic acid) which was selected as a potential follow‐up of setipiprant (ACT‐129968). Our endeavor toward the identification of potent and safe CRTH2 receptor antagonists starting from setipiprant (ACT‐129968) is reported. An unexpected and surprising discovery was that all unwanted safety issues observed with the very potent antagonist (S)‐B‐1 (ACT‐453859) could be overcome by the replacement of one aromatic CH group by an aromatic nitrogen atom to result in (S)‐72 (ACT‐774312) which was clinically investigated in subjects with bilateral nasal polyposis.