Discovery of IDOR-1117-1680, a dual orexin receptor antagonist with fast onset and short duration of action for the treatment of insomnia.

We describe the optimization of 2-acyl-1-biarylmethylpyrazolidines, a novel class of dual orexin receptor antagonists (DORAs) designed for the treatment of sleep disorders requiring a rapid onset (<30 min) and a short duration of action (2-4 h). Building on the previously identified lead compound DORA 4, our optimization program yielded several potent pyrazolidine DORAs with carefully tailored in vitro physicochemical and DMPK (drug, metabolism and pharmacokinetics) properties. In vivo studies in animals, combined with pharmacokinetic-pharmacodynamic (PK-PD) simulations, demonstrated that DORA 31 and DORA (R)-38 effectively induced sleep in dogs and met the in silico predicted requirements for rapid onset and short duration in humans.

Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases.

Migration of immune cells to sites of inflammation is a critical step in the body's response to infections but also during autoimmune flares. Chemokine receptors, members of the GPCR receptors, are instrumental in directing specific cell types to their target organs. Herein, we describe a highly potent small molecule antagonist of the chemokine receptor CCR6, which came out of fine-tuned structural elaborations from a proprietary HTS hit.