SR9009

022-05-19: reference:

SR9009 (Stenabolic) #

• Rev-Erb-α ligand. This is epic because it basically potentiates proper cicadian rhythm.
• Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour this is one of the main studies, I believe.
  • I need to take a close look at the comparison between the 2. They might have slightly new effects?
• SR9009 has REV-ERB–independent effects on cellproliferation and metabolism
  • SR9009 can decrease cell viability, rewire cellular metabolism, and alter gene transcription in hepatocytes and embryonicstem cells lacking both REV-ERBαand -β.
• Regulation of Circadian Behavior and Metabolism by Synthetic REV-ERB Agonists
  • In addition to the decrease in fat mass we also observed a12% decrease in plasma triglycerides (TGs) and a 47% decrease in plasma total cholesterol (Chol) (Fig. 5c). Plasma non-esterified fatty acids (NEFA) were also reduced (23%) along with plasma glucose (19%) in the SR9009 treated animals (Fig. 5c). There was also a trend toward a decrease in plasma insulin levels (35%). Consistent with the decrease in adipocity we also noted an 80% decrease in plasma leptin and a decrease (72%) in the proinflammatory cytokine IL-6
  • Treatment resulted increased glucose oxidation in addition to fatty acid oxidation
• SR9009 inhibits lethal prostate cancer subtype 1 by regulating the LXRα/FOXM1 pathway independently of REV-ERBs
  • Somehow induces LXRα → blocks FOXM1, which is an inducer of PCS1 (a driver of prostate cancer) amongst other things.
    • (This could be awesome since LXR in the brain is neurogenic)
• No effect on insulin sensitivity. Lowers cholesterol.
• Strong anxiolytic without any depressive/GABAergic effect.
  • Could be due to Rev-Erb inhibiting NPAS2
• REV-ERBβ is required to maintain normal wakefulness and the wake-inducing effect of dual REV-ERB agonist SR9009
  • REV-ERBβ-deficient mice administered with dual REV-ERB agonist SR9009, failed to show drug-induced wake increase
• Rev-erbα agonist SR9009 protects against cerebral ischemic injury through mechanisms involving Nrf2 pathway (Mar 2023)
• Identification of a small molecule SR9009 that activates NRF2 to counteract cellular senescence (2021)
  • Activates NRF2 pathway.
  • 
    • RNA sequencing data confirmed that the elevated SASP factors were reduced by SR9009, including IL-1α, IL-1β, IL-8, IL-6, and CXCL-1.
  • Attenuated p38.
  • Weakened NF-κB and PI3K-AKT pathways.
• REV-ERB Agonist SR9009 Regulates the Proliferation and Neurite Outgrowth/Suppression of Cultured Rat Adult Hippocampal Neural Stem/Progenitor Cells in a Concentration-Dependent Manner
  • Inhibited the growth of these AHPs.
  • 9009 activated Rev-Erbβ downstream genes like Ccna2 (there’s another CCNA?) and Sez6 (and I say 7).
    • Ccna2 = Cyclin A2. Promotes proliferation.
    • Sez6 promotes neurite outgrowth
• REV-ERB agonism improves liver pathology in a mouse model of NASH
  • Recruits Ncor1 (Nuclear receptor co-repressor 1).
• Pharmacological and Genetic Modulation of REV-ERB Activity and Expression Affects Orexigenic Gene Expression (2016)
  • Not only orexin, but it also strongly represses transcription of the orexin receptors.
  • Orexin signaling via OX1R in the striatum and nucleus accumbens is associated with reward feeding and addictive behavior toward nicotine and other drugs. SR9009 thus prevents this.
  • I wonder it this provides some insight into inconsistency from Modafinil, given how the wakefulness-promoting effect is enhanced in orexin-KO and everything.
• mTOR inhibitor.
• SR9009 induces a REV-ERB dependent anti-small-cell lung cancer effect through inhibition of autophagy
  • Via what exactly? Repressing Atg5
• Identification of a small molecule SR9009 that activates NRF2 to counteract cellular senescence
  • SASP suppressor (via activating NRF2) , inhibiting senescence.
• Rev-erb-α regulates atrophy-related genes to control skeletal muscle mass
  • KO mice have increased expression of muscle atrophy-related genes (atrogenes), while over-expression = increased muscle size.
• Suppression of atherosclerosis by synthetic REV-ERB agonist
  • reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis
  • Reduced the polarization of bone marrow-derived mouse macrophages to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages
• REV-ERBα Regulates TH17 Cell Development and Autoimmunity Reduces incidence of autoimmunity.

• According to tyw’s citiation that is 404, it peaks around 10 PM - noon? ZT0 (zeitgeber time) = midnight to the system being studied, which is the opposite between mice and humans I suppose.
  • (This post is a fantastic writeup on SR9009 though)

Metabolism #

• No reported negative side effects afaik brotha.
• α IC50 = 670 nM and αβ IC50 = 800
• In vitro metabolism of the REV-ERB agonist SR-9009 and subsequent detection of metabolites in associated routine equine plasma and urine doping control samples
  • To the best of the authors’ knowledge, this is the first report of an adverse analytical finding in an equine sample for SR-9009 or its metabolites in equine doping control.
    • Adverse meaning what exactly? Besides having evidence of administration. Since some studies it was undetected in urine.
• CYP stuff. A further insight into the metabolic profile of the nuclear receptor Rev-erb agonist, SR9009

SR9011 #

• There are ohter rev-erb-α ligands. For one thing, this has better bioavailability. Sonething like 5x? Idk if this matters when intranasal, though aerin has recommended intranasal for all of them.
• (α IC50 = 970 nM and αβ IC50 = 790)
• Far less studied. Idk, I’ll check it out some other time maybe? It’s hard to say what the differences are without going deep asf. I guess I’ll see what’s different between α and β.

SR10067 (1380548-06-2) #

Also has strong Rev-Erb-β affinity. And something like 6-8x more potent in general.

Dose #

• 6-20mg intranasal. (Blank et al. always did 10mg) 4 hour half-life. Pretty poor oral bioavailability. Nasal spray (in C8) or I believe ideally injected.
  • Just did 25mg/mL (250mg in 5mL). It was looking a bit chunky, and still kind of is. I chopped it up first but clearly it’s probably a matter of stability
    • 600 mg / 25mg/mL = 24mL of liquid
    • Swiss says 1g in 30mL of bromantane spray was no problem. It’s supposed to be highly lipophilic
• No tolerance/dependency. Inhibits cocaine addiction.
• Umbrella labs has SR9009/SR9011 for $70/g. Chemyo is also $70/g for SR9009, but $100 for SR9011. So umbrella 9011 might be the best bang for your buck. $1/g from PGLChem.
• It technically has a ~30 minute half life, but its downstream effects on the cirdadian rhythm last like 12+ hours.