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

Neuroactive steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABAA receptor (GABAA-R). Herein we report the effects on the activity and pharmacokinetic properties of a series of nor-19 pregnanolone analogues bearing a heter...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2015-04, Vol.58 (8), p.3500-3511
Main Authors: Martinez Botella, Gabriel, 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
Format: Article
Language:English
Subjects:
Allosteric Regulation - drug effects
Animals
Humans
Mice
Neurotransmitter Agents - chemistry
Neurotransmitter Agents - pharmacokinetics
Neurotransmitter Agents - pharmacology
Pregnanolone - analogs & derivatives
Pregnanolone - pharmacokinetics
Pregnanolone - pharmacology
Rats
Receptors, GABA - metabolism
Structure-Activity Relationship
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Summary:Neuroactive steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABAA receptor (GABAA-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 GABAA receptor modulator, and SGE-872, a selective extrasynaptic GABAA receptor modulator. Both molecules possess excellent druglike properties, making them advanced leads for oral delivery of GABAA receptor modulators.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b00032