title: Neuroactive Steroids. 1. Positive Allosteric Modulators of the (γ-Aminobutyric Acid)A Receptor: Structure-Activity Relationships of Heterocyclic Substitution at C-21.
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.
authors: †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
authors: Gabriel
authors: G
authors: Martinez Botella
authors: †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
authors: Francesco G
authors: FG
authors: Salituro
authors: †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
authors: Boyd L
authors: BL
authors: Harrison
authors: ‡Shanghai Chempartner, 998 Halei Road, Shanghai, China 201203.
authors: Richard T
authors: RT
authors: Beresis
authors: §WuXi AppTec, 288 Fute Zhong Road, Shanghai, China 200131.
authors: Zhu
authors: Z
authors: Bai
authors: ‡Shanghai Chempartner, 998 Halei Road, Shanghai, China 201203.
authors: Kaisheng
authors: K
authors: Shen
authors: †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
authors: Gabriel M
authors: GM
authors: Belfort
authors: †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
authors: Carlos M
authors: CM
authors: Loya
authors: †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
authors: Michael A
authors: MA
authors: Ackley
authors: †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
authors: Scott J
authors: SJ
authors: Grossman
authors: †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
authors: Ethan
authors: E
authors: Hoffmann
authors: ‡Shanghai Chempartner, 998 Halei Road, Shanghai, China 201203.
authors: Shiling
authors: S
authors: Jia
authors: ‡Shanghai Chempartner, 998 Halei Road, Shanghai, China 201203.
authors: Jiamiao
authors: J
authors: Wang
authors: †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
authors: James J
authors: JJ
authors: Doherty
authors: †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
authors: Albert J
authors: AJ
authors: Robichaud
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D006801:Humans; D051379:Mice; D018377:Neurotransmitter Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018079:Receptors, GABA / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018377:Neurotransmitter Agents; D018079:Receptors, GABA; D011280:Pregnanolone