Discovery, synthesis and SAR of 3-aryl pyrazolidines, novel dual orexin receptor antagonists for the treatment of sleep disorders

Abstract

We report a facet of the drug discovery program aimed at identifying dual orexin receptor antagonists (DORAs) suitable for treating sleep disorders requiring a fast onset of action (<30 min) and a short duration of the hypnotic effect (2–4 h). Starting from the previously disclosed orexin antagonist (+)-6, we designed a novel and potent DORA, the 3-aryl pyrazolidine (+)-7. With the objective of identifying 3-aryl pyrazolidine DORAs that could back-up our preclinical candidate IDOR-1117-1680 DORA 5, we established structure-activity relationships (SAR) of the three motives substituting the pyrazolidine core of (+)-7. These investigations afforded DORA (+)-27, whose dog pharmacokinetic (PK) parameters were not supportive of further in vivo studies. Additional investigations afforded DORA (+)-33, a 3-aryl pyrazolidine demonstrating improved dog PK parameters and achieving in silico fast and short-action pharmacological requirements. DORA (+)-33 demonstrated in vivo efficacy in a rat sleep model but it time-dependently inhibited CYP3A4 so its advancement to further in vivo studies was halted.