ACT-462206

• CAT Number: I000365
• CAS Number: 1361321-96-1
• Molecular Formula: C20H24N2O4S
• Molecular Weight: 388.48
• Purity: ≥95%
• Synonyms: (2S)-N-(3,5-dimethylphenyl)-1-(4-methoxyphenyl)sulfonylpyrrolidine-2-carboxamide
• InChI: InChI=1S/C20H24N2O4S/c1-14-11-15(2)13-16(12-14)21-20(23)19-5-4-10-22(19)27(24,25)18-8-6-17(26-3)7-9-18/h6-9,11-13,19H,4-5,10H2,1-3H3,(H,21,23)/t19-/m0/s1
• InChIKey: NHPQGZOBHSVTAQ-IBGZPJMESA-N
• SMILES: CC1=CC(=CC(=C1)NC(=O)C2CCCN2S(=O)(=O)C3=CC=C(C=C3)OC)C

ACT-462206 is an orally active and potent dual Orexin 1/Orexin 2 receptor antagonist with IC50s of 60 nM (Orexin 1) and 11 nM (Orexin 2), respectively. ACT-462206 exhibits brain penetration properties, and can be used for insomnia, stress/anxiety-related disorders and addiction research[1].
Orexins are released in a Ca2+-sensitive manner at axonal terminals and can then bind to two closely related G-protein-coupled receptors (GPCRs): orexin receptor type 1 (OX1) and orexin receptor type 2 (OX2)[1].
ACT-462206 shows binding affinity with Kbs of 17 nM (hOX1), 2.4 nM (hOX2), 28 nM (rOX1), 9.9 nM (rOX2), 27 nM (dOX1), 4.2 nM (dOX2), respectively[1].
ACT-462206 inhibits Orexin activity with IC50s of 60 nM (hOX1), 11 nM (hOX2), 48 nM (rOX1), 9.6 nM (rOX2), 68 nM (dOX1), 26 nM (dOX2), respectively[1].
ACT-462206 inhibits CYP450 3A4T and 3A4M with IC50s of 15 μM and 29 μM, respectively[1].
ACT-462206 (compound 24) (100 mg/kg; p.o.; sampling at 3 h) can go cross blood brain barrier, with concentrations are 2267 ng/mL and 1219 ng/g in plasma and brain, respectively in male Wistar rats[1].
ACT-462206 (10-300 mg/kg; p.o.; single dose) shows sleep-promoting effects in male Wistar rats and in male Beagle dogs, with decreasing wakefulness and increasing non-rapid eye movement (non-REM) and REM sleep[1].
ACT-462206 (100, 300 mg/kg; p.o.; single dose) exerts anxiolytic-like effects, decreases the fear-potentiated startle reflexes in response to a sudden loud noise in rats, reduces the socialstress-induced increases of locomotion, body temperature, and heart rate[1].
Pharmacokinetics in different species[1]

Route
Dose (mg/kg)
AUC (ng•h/mL)
CL (mL/min/kg)
Vss (L/kg)
t1/2 (h)
cmax (ng/mL)
tmax (h)
F1/2 (%)

rat
i.v.
1
586
29
1.8
1.9
/
/
/

p.o.
10
2310
/
/
/
1600
0.5
39

dog
i.v.
1
1490
11
1.4
1.7
/
/
/

p.o.
3
2750
/
/
/
426
0.5
52

Reference

[1]. Boss C, et al. Structure-activity relationship, biological, and pharmacological characterization of the proline sulfonamide ACT-462206: a potent, brain-penetrant dual orexin 1/orexin 2 receptor antagonist. ChemMedChem. 2014 Nov;9(11):2486-96.
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