Journal of Medicinal Chemistry p. 7810 - 7819 (2017)
Update date:2022-08-17
Topics:
Martinez Botella, Gabriel
Salituro, Francesco G.
Harrison, Boyd L.
Beresis, Richard T.
Bai, Zhu
Blanco, Maria-Jesus
Belfort, Gabriel M.
Dai, Jing
Loya, Carlos M.
Ackley, Michael A.
Althaus, Alison L.
Grossman, Scott J.
Hoffmann, Ethan
Doherty, James J.
Robichaud, Albert J.
Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABAA 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-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217, 3), a potent GABAA 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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