2 research outputs found

    Neuroactive Steroids. 1. Positive Allosteric Modulators of the (γ-Aminobutyric Acid)<sub>A</sub> Receptor: Structure–Activity Relationships of Heterocyclic Substitution at C‑21

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    Neuroactive steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABA<sub>A</sub> receptor (GABA<sub>A</sub>-R). Herein we report the effects on the activity and pharmacokinetic properties of a series of nor-19 pregnanolone analogues bearing a heterocyclic substituent at C-21. These efforts resulted in the identification of SGE-516, a balanced synaptic/extrasynaptic GABA<sub>A</sub> receptor modulator, and SGE-872, a selective extrasynaptic GABA<sub>A</sub> receptor modulator. Both molecules possess excellent druglike properties, making them advanced leads for oral delivery of GABA<sub>A</sub> receptor modulators

    Neuroactive Steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano‑1<i>H</i>‑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)<sub>A</sub> Receptor

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    Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABA<sub>A</sub> receptors. Herein, we report new SAR insights in a series of 5β-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3α-hydroxy-3β-methyl-21-(4-cyano-1<i>H</i>-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217, <b>3</b>), a potent GABA<sub>A</sub> receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties. Compound <b>3</b> has completed a phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial and is currently being studied in parallel phase 2 clinical trials for the treatment of postpartum depression (PPD), major depressive disorder (MDD), and essential tremor (ET)
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