Zuranolone also known as SAGE-217, is a potent GABAA receptor agonist with EC50 values of 296 nM and 163 nM for α1β2γ2 and α4β3δ GABAA receptors. Zuranolone shows >30 μM inhibition in a cardiac panel of eight relevant cardiac ion channels. In vivo, Zuranolone (0.3-5 mg/kg, i.v.) in the rat model of status epilepticus (SE) abolishes both behavioral and electrographic seizure activity, even when administered 60 min after induction of SE. Additional PK studies of Zuranolone in dog show low clearance (<10% of hepatic blood flow), resulting in excellent 68% oral bioavailability.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO 82 mg/mL|
Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABA A receptor positive allosteric modulator
Alison L Althaus, et al. Neuropharmacology. 2020 Dec 15;181:108333. PMID: 32976892.
Neuroactive Steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5β-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (γ-Aminobutyric Acid) A Receptor
Gabriel Martinez Botella, et al. J Med Chem. 2017 Sep 28;60(18):7810-7819. PMID: 28753313.
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