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. Further analysis of their covalent binding potential in human hepatocytes prioritized DORA 31 as the preferred molecule for additional safety and biopharmaceutical evaluation. In this report we summarize and present the results of all studies that supported the selection of DORA 31 (IDOR-1117-1680) as a preclinical development candidate.