2. Academic Validation
  3. Neuroactive Steroids. 1. Positive Allosteric Modulators of the (γ-Aminobutyric Acid)A Receptor: Structure-Activity Relationships of Heterocyclic Substitution at C-21

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

  • J Med Chem. 2015 Apr 23;58(8):3500-11. doi: 10.1021/acs.jmedchem.5b00032.
Gabriel Martinez Botella 1,  Francesco G Salituro 1,  Boyd L Harrison 1,  Richard T Beresis 2,  Zhu Bai 3,  Kaisheng Shen 2,  Gabriel M Belfort 1,  Carlos M Loya 1,  Michael A Ackley 1,  Scott J Grossman 1,  Ethan Hoffmann 1,  Shiling Jia 2,  Jiamiao Wang 2,  James J Doherty 1,  Albert J Robichaud 1
Affiliations

Affiliations

  • 1 †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
  • 2 ‡Shanghai Chempartner, 998 Halei Road, Shanghai, China 201203.
  • 3 §WuXi AppTec, 288 Fute Zhong Road, Shanghai, China 200131.
PMID: 25799373 DOI: 10.1021/acs.jmedchem.5b00032
Abstract

Neuroactive Steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABA(A) receptor (GABA(A)-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(A) receptor modulator, and SGE-872, a selective extrasynaptic GABA(A) receptor modulator. Both molecules possess excellent druglike properties, making them advanced leads for oral delivery of GABA(A) receptor modulators.

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