Neuroactive Steroids. 2. 3alpha-Hydroxy-3beta-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5beta-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (gamma-Aminobutyric Acid)(A) Receptor.

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Martinez Botella G, Salituro FG, Harrison BL, Beresis RT, Bai Z, Blanco MJ, Belfort GM, Dai J, Loya CM, Ackley MA, Althaus AL, Grossman SJ, Hoffmann E, Doherty JJ, Robichaud AJ

Neuroactive Steroids. 2. 3alpha-Hydroxy-3beta-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5beta-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (gamma-Aminobutyric Acid)(A) Receptor.

J Med Chem. 2017 Sep 28;60(18):7810-7819. doi: 10.1021/acs.jmedchem.7b00846. Epub 2017 Aug 17.

PubMed ID
28753313 [ View in PubMed
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Abstract

Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABA(A) receptors. Herein, we report new SAR insights in a series of 5beta-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3alpha-hydroxy-3beta-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5beta-pregnan-20-one (SAGE-217, 3), a potent GABA(A) receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties. Compound 3 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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