Fazamorexant

An effort toward the synthesis and process development of the orexin receptor antagonist YZJ-1139 I was described in this article.I contains the azabicyclic nortropane structure with three chiral centers.By the original process, highly pure intermediates or API could be obtained by chromatog. with a relatively low yield.To remove the undesirable stereoisomers as early as possible, an N-(R)-α-phenethyl was synthesized by the Robinson-Schopf reaction and easily purified as its hydrochloride.The single crystal X-ray study was used to confirm the stereo configuration of I.The protecting group could be easily removed by transfer hydrogenation, resulting in an enantiomerically pure intermediate as its D-tartrate.The overall yield for preparing I was significantly increased, and this cost-efficient process might be promising in future com. productions.

Fazamorexant is a dual orexin receptor antagonist being developed for the treatment of insomnia. This study aims to determine the dose‐exposure‐response relationship of single‐dose fazamorexant vs . zolpidem in young adult and elderly healthy Chinese volunteers.

This single‐centre, randomized, double‐blind, double‐dummy, placebo‐ and active‐controlled, 4‐period crossover study administered fazamorexant (40 mg/80 mg to young adults; 20 mg/40 mg to the elderly) and zolpidem (10 mg). Pharmacokinetics, pharmacodynamics (primary endpoint: SPV) and safety were assessed.

Following a single 40 mg oral dose of fazamorexant in elderly and young adults, the geometric least‑squares mean (GLSM) values for C max were 1527.05 ng/mL (95% CI: 1268.66–1838.06) in the elderly and 1652.52 ng/mL (95% CI: 1420.41–1922.56) in young adults. The corresponding GLSM AUC 0–t values were 7815.91 h·ng/mL (95% CI: 5985.56–10205.97) and 8351.15 h·ng/mL (95% CI: 6716.38–10383.84), respectively. There was no significant pharmacokinetic difference between young adults and the elderly with fazamorexant (C max GMR 92.41% [90% CI: 75.84–112.59]; AUC 0‐t GMR 93.59% [90% CI: 70.43–124.37]). In general, high‐dose fazamorexant caused similar or less impairment vs . zolpidem in eye movements (SPV: young adults: 110.4 ± 80.1 vs . 108.3 ± 82.7 deg/sec；elderly: 145.1 ± 64.2 vs . 185.5 ± 63.0 deg/sec), choice‐reaction‐time performance, body sway and memory tests in young and elderly cohorts. The effects of low‐dose fazamorexant on these psychomotor and cognitive measurements were significantly smaller than those of high‐dose fazamorexant and zolpidem in both age cohorts. Despite of similarity in exposure, fazamorexant demonstrated larger effects on the pharmacodynamic measurements in the elderly than in young adults, suggesting an age‐related increase of pharmacological sensitivity.

Clinically hypnotic doses of fazamorexant induced less balance, judgement and memory impairment in healthy adults and elderly volunteers compared to the comprehensive suppression of zolpidem on the neurological system. These preliminary results suggest that fazamorexant is a potentially safer drug for insomnia. No age‐related pharmacokinetic difference was identified with fazamorexant.