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：96

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

共 30 条

[1] Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors [J].

Abramian, Armen M. ;

Comenencia-Ortiz, Eydith ;

Modgil, Amit ;

Vien, Thuy N. ;

Nakamura, Yasuko ;

Moore, Yvonne E. ;

Maguire, Jamie L. ;

Terunuma, Miho ;

Davies, Paul A. ;

Moss, Stephen J. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (19) :7132-7137

[2]

Althaus A. L., UNPUB

[3] Two tyrosine residues on the alpha subunit are crucial for benzodiazepine binding and allosteric modulation of gamma-aminobutyric acid(A) receptors [J].

Amin, J ;

BrooksKayal, A ;

Weiss, DS .

MOLECULAR PHARMACOLOGY, 1997, 51 (05) :833-841

[4]

[Anonymous], 2015, STUD SAGE 547 SUP RE

[5] Extrasynaptic GABAA Receptors: Form, Pharmacology, and Function [J].

Belelli, Delia ;

Harrison, Neil L. ;

Maguire, Jamie ;

Macdonald, Robert L. ;

Walker, Matthew C. ;

Cope, David W. .

JOURNAL OF NEUROSCIENCE, 2009, 29 (41) :12757-12763

[6]

Bialer M, 2017, EPILEPSIA, V58, P181, DOI [10.1111/epi.14557, 10.1111/epi.13634]

[7] Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT XII) [J].

Bialer, Meir ;

Johannessen, Svein I. ;

Levy, Rene H. ;

Perucca, Emilio ;

Tomson, Torbjorn ;

White, H. Steve .

EPILEPSY RESEARCH, 2015, 111 :85-141

[8] Neuroactive Steroids. 1. Positive Allosteric Modulators of the (γ-Aminobutyric Acid)A Receptor: Structure-Activity Relationships of Heterocyclic Substitution at C-21 [J].

Botella, Gabriel Martinez ;

Salituro, Francesco G. ;

Harrison, Boyd L. ;

Beresis, Richard T. ;

Bai, Zhu ;

Shen, Kaisheng ;

Belfort, Gabriel M. ;

Loya, Carlos M. ;

Ackley, Michael A. ;

Grossman, Scott J. ;

Hoffmann, Ethan ;

Jia, Shiling ;

Wang, Jiamiao ;

Doherty, James J. ;

Robichaud, Albert J. .

JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (08) :3500-3511

[9] GABAergic dysfunction in mood disorders [J].

Brambilla, P ;

Perez, J ;

Barale, F ;

Schettini, G ;

Soares, JC .

MOLECULAR PSYCHIATRY, 2003, 8 (08) :721-737

[10]

Ellenbogen A, 2016, NEUROLOGY, V86

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