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

被引：93

作者：

Botella, Gabriel Martinez ^{[1
,4
]}

Salituro, Francesco G. ^{[1
]}

Harrison, Boyd L. ^{[1
]}

Beresis, Richard T. ^{[2
]}

Bai, Zhu ^{[3
]}

Blanco, Maria-Jesus ^{[1
]}

Belfort, Gabriel M. ^{[1
,5
]}

Dai, Jing ^{[1
]}

Loya, Carlos M. ^{[1
,6
]}

Ackley, Michael A. ^{[1
]}

Althaus, Alison L. ^{[1
]}

Grossman, Scott J. ^{[1
]}

Hoffmann, Ethan ^{[1
]}

Doherty, James J. ^{[1
]}

Robichaud, Albert J. ^{[1
]}

机构：

[1] Sage Therapeut Inc, 215 First St, Cambridge, MA 02142 USA

[2] Shanghai Chempartner, 998 Halei Rd, Shanghai 201203, Peoples R China

[3] WuXi AppTec, 288 Fute Zhong Rd, Shanghai 200131, Peoples R China

[4] Praxis Precis Med, Cambridge, MA USA

[5] Takeda Pharmaceut Inc, Osaka, Japan

[6] Collegium Pharmaceut Inc, Canton, MA USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 18期

关键词：

GABA(A) RECEPTORS; ANTIEPILEPTIC DRUGS; EILAT CONFERENCE; PROGRESS REPORT; NEUROSTEROIDS; BINDING; SUBUNIT;

D O I：

10.1021/acs.jmedchem.7b00846

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 5 beta-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3 alpha-hydroxy-3 beta-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5 beta-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).

引用

页码：7810 / 7819

页数：10

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