The metabolism and pharmacokinetics of [¹⁴C]-S-777469, a new cannabinoid receptor 2 selective agonist, in healthy human subjects

Abstract

1. The metabolism and pharmacokinetics of S-777469 were investigated after a single oral administration of [14C]-S-777469 to healthy human subjects. 2. Total radioactivity was rapidly and well absorbed in humans, with Cmax of 11,308 ng eq. of S-777469/ml at 4.0 h. The AUCinf ratio of unchanged S-777469 to total radioactivity was approximately 30%, indicating that S-777469 was extensively metabolized in humans. 3. The metabolite profiling in human plasma showed that S-777469 5-carboxymethyl (5-CA) and S-777469 5-hydroxymethyl (5-HM) were the main circulating metabolites, and the AUCinf ratio of 5-CA and 5-HM to total radioactivity were 24 and 9.1%, respectively. These data suggest that S-777469 was subsequently metabolized to 5-CA in humans although the production amount of 5-CA was extremely low in human hepatocytes. 4. Total radioactivity was mainly excreted via the feces, with 5-CA and 5-HM being the main excretory metabolites in feces and urine. Urinary excretion of 5-CA was comparable with that of 5-HM, whereas fecal excretion of 5-CA was lower than that of 5-HM. 5. In conclusion, the current mass balance study revealed the metabolic and pharmacokinetic properties of S-777469 in humans. These data should be useful to judge whether or not the safety testing of metabolite of S-777469 is necessary.

Toxicokinetics of new psychoactive substances: plasma protein binding, metabolic stability, and human phase I metabolism of the synthetic cannabinoid WIN 55,212‐2 studied using in vitro tools and LC‐HR‐MS/MS

“…To our knowledge, no data is available on human metabolism or urinary and fecal excretion rates of WIN55,212‐2. However, CB2 agonist have previously been shown to be excreted in feces to a large extend . Examples on the MS 2 spectra and fragmentation pathways of the metabolites are presented in Figure .…”

“…However, CB2 agonist have previously been shown to be excreted in feces to a large extend. [26] Examples on the MS 2 spectra and fragmentation pathways of the metabolites are presented in Figure 1b. No metabolites could be detected in the blank samples.…”

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

“…117,118 S-777,469 completed Phase II trials for atopic dermatitis in 2011, but no clinical data or future plans for clinical testing of this compound have been released, indicating that its development may have been halted. [119][120][121] After several failed clinical trials, the possibility that years of immunostaining results were inaccurate and halted CB2 research programs, the progress of CB2-targeted therapeutics was seemingly at an impasse. Research efforts into therapeutic potential of CB2 selective agonists have recently focused on improving selectivity by several orders of magnitude.…”

“…117,118 S-777,469 completed Phase II trials for atopic dermatitis in 2011, but no clinical data or future plans for clinical testing of this compound have been released, indicating that its development may have been halted. 119–121…”

Medicinal Chemistry, Pharmacology, and Potential Therapeutic Benefits of Cannabinoid CB2 Receptor Agonists

“…Shionogi & Co. investigated several novel CB 2 agonists and among them the compound S-777469 or raclopride as a CB 2 -selective agonist for clinical development. This compound is considered to be a promising candidate for an orally active antipruritic effect since it significantly inhibited histamine-induced peripheral nerve firing in mice, suggesting that S-777469 produces its antipruritic effects by inhibiting itch signal transmission through CB 2 agonism. , The metabolism and pharmacokinetics of S-777469 were investigated after a single oral administration of [ 14 C]-S-777469 to healthy human subjects and showed a total radioactivity which was rapid and well absorbed in humans …”